Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors

ABSTRACT

In its many embodiments, the present invention provides a novel class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the CDKs using such compounds or compositions.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.11/710,644 filed Feb. 23, 2007, which is a divisional of applicationSer. No. 11/245,401 filed Oct. 6, 2005 (now U.S. Pat. No. 7,196,078),which in turn is a Continuation-in-Part of U.S. patent application Ser.No. 10/776,988, filed Feb. 11, 2004 (now U.S. Pat. No. 7,119,200), whichis a Continuation-in-Part of U.S. patent application Ser. No. 10/654,546filed Sep. 3, 2003 (now U.S. Pat. No. 7,161,003), which claims priorityto U.S. provisional patent applications, Ser. Nos. 60/408,027 filed Sep.4, 2002 and 60/421,959 filed Oct. 29, 2002.

FIELD OF THE INVENTION

The present invention relates to pyrazolo[1,5-a]pyrimidine compoundsuseful as protein kinase inhibitors (such as for example, the inhibitorsof the cyclin-dependent kinases, mitogen-activated protein kinase(MAPK/ERK), glycogen synthase kinase 3(GSK3beta) and the like),pharmaceutical compositions containing the compounds, and methods oftreatment using the compounds and compositions to treat diseases suchas, for example, cancer, inflammation, arthritis, viral diseases,neurodegenerative diseases such as Alzheimer's disease, cardiovasculardiseases, and fungal diseases. This application claims benefit ofpriority from U.S. provisional patent applications, Ser. No. 60/408,027filed Sep. 4, 2002, and Ser. No. 60/421,959 filed Oct. 29, 2002.

BACKGROUND OF THE INVENTION

Protein kinase inhibitors include kinases such as, for example, theinhibitors of the cyclin-dependent kinases (CDKs), mitogen activatedprotein kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta), andthe like. Protein kinase inhibitors are described, for example, by M.Hale et al in WO02/22610 A1 and by Y. Mettey et al in J. Med. Chem.,(2003) 46 222-236. The cyclin-dependent kinases are serine/threonineprotein kinases, which are the driving force behind the cell cycle andcell proliferation. Individual CDK's, such as, CDK1, CDK2, CDK3, CDK4,CDK5, CDK6 and CDK7, CDK8, CDK9 and the like, perform distinct roles incell cycle progression and can be classified as either G1, S, or G2Mphase enzymes. Uncontrolled proliferation is a hallmark of cancer cells,and misregulation of CDK function occurs with high frequency in manyimportant solid tumors. CDK2 and CDK4 are of particular interest becausetheir activities are frequently misregulated in a wide variety of humancancers. CDK2 activity is required for progression through G1 to the Sphase of the cell cycle, and CDK2 is one of the key components of the G1checkpoint. Checkpoints serve to maintain the proper sequence of cellcycle events and allow the cell to respond to insults or toproliferative signals, while the loss of proper checkpoint control incancer cells contributes to tumorgenesis. The CDK2 pathway influencestumorgenesis at the level of tumor suppressor function (e.g. p52, RB,and p27) and oncogene activation (cyclin E). Many reports havedemonstrated that both the coactivator, cyclin E, and the inhibitor,p27, of CDK2 are either over- or underexpressed, respectively, inbreast, colon, nonsmall cell lung, gastric, prostate, bladder,non-Hodgkin's lymphoma, ovarian, and other cancers. Their alteredexpression has been shown to correlate with increased CDK2 activitylevels and poor overall survival. This observation makes CDK2 and itsregulatory pathways compelling targets for the development years, anumber of adenosine 5′-triphosphate (ATP) competitive small organicmolecules as well as peptides have been reported in the literature asCDK inhibitors for the potential treatment of cancers. U.S. Pat. No.6,413,974, col. 1, line 23-col. 15, line 10 offers a good description ofthe various CDKs and their relationship to various types of cancer.

CDK inhibitors are known. For example, flavopiridol (Formula I) is anonselective CDK inhibitor that is currently undergoing human clinicaltrials, A. M. Sanderowicz et al, J. Clin. Oncol. (1998) 16, 2986-2999.

Other known inhibitors of the CDKs include, for example, olomoucine (J.Vesely et al, Eur. J. Biochem., (1994) 224, 771-786) and roscovitine (I.Meijer et al, Eur. J. Biochem., (1997) 243, 527-536). U.S. Pat. No.6,107,305 describes certain pyrazolo[3,4-b]pyridine compounds as CDKinhibitors. An illustrative compound from the '305 patent has theFormula II:

K. S. Kim et al, J. Med. Chem. 45 (2002) 3905-3927 and WO 02/10162disclose certain aminothiazole compounds as CDK inhibitors.

Pyrazolopyrimidines are known. For Example, WO92/18504, WO02/50079,WO95/35298, WO02/40485, EP94304104.6, EP0628559 (equivalent to U.S. Pat.Nos. 5,602,136, 5,602,137 and 5,571,813), U.S. Pat. No. 6,383,790, Chem.Pharm. Bull., (1999) 47 928, J. Med. Chem., (1977) 20, 296, J. Med.Chem., (1976) 19 517 and Chem. Pharm. Bull., (1962) 10 620 disclosevarious pyrazolopyrimidines. Other publications of interest are: WO03/101993 (published Dec. 11, 2003), WO 03/091256 (published Nov. 6,2003), and DE 10223917 (published Dec. 11, 2003).

There is a need for new compounds, formulations, treatments andtherapies to treat diseases and disorders associated with CDKs. It is,therefore, an object of this invention to provide compounds useful inthe treatment or prevention or amelioration of such diseases anddisorders.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a novel class ofpyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependentkinases, methods of preparing such compounds, pharmaceuticalcompositions comprising one or more such compounds, methods of preparingpharmaceutical formulations comprising one or more such compounds, andmethods of treatment, prevention, inhibition or amelioration of one ormore diseases associated with the CDKs using such compounds orpharmaceutical compositions.

In one aspect, the present application discloses a compound, orpharmaceutically acceptable salts or solvates of said compound, saidcompound having the general structure shown in Formula III:

wherein:

R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl,cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl,heterocyclylalkyl, heteroarylalkyl (including N-oxide of saidheteroaryl), —(CHR⁵)_(n)-aryl, —(CHR⁵)_(n)-heteroaryl,

wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, and heteroaryl can be unsubstituted or optionallysubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from the groupconsisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF₃,OCF₃, CN, —OR⁵, —NR⁵R¹⁰, —C(R⁴R⁵)_(p)—R⁹, —N(R⁵)Boc, —(CR⁴R⁵)_(p)OR⁵,—C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R¹⁰, —SO₃H, —SR¹⁰, —S(O₂)R⁷, —S(O₂)NR⁵R¹⁰,—N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R¹⁰;

R² is selected from the group consisting of H, R⁹, alkyl, alkenyl,alkynyl, CF₃, heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl,arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkylsubstituted with 1-6 R⁹ groups which can be the same or different andare independently selected from the list of R⁹ shown below, arylsubstituted with 1-3 aryl or heteroaryl groups which can be the same ordifferent and are independently selected from phenyl, pyridyl,thiophenyl, furanyl and thiazolo groups, aryl fused with an aryl orheteroaryl group, heteroaryl substituted with 1-3 aryl or heteroarylgroups which can be the same or different and are independently selectedfrom phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups,heteroaryl fused with an aryl or heteroaryl group,

wherein one or more of the aryl and/or one or more of the heteroaryl inthe above-noted definitions for R² can be unsubstituted or optionallysubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from the groupconsisting of halogen, —CN, —OR⁵, —SR⁵, —S(O₂)R⁶, —S(O₂)NR⁵R⁶, —NR⁵R⁶,—C(O)NR⁵R⁶, CF₃, alkyl, aryl and OCF₃;

R³ is selected from the group consisting of H, halogen, —NR⁵R⁶, —OR⁶,—SR⁶, —C(O)N(R⁵R⁶), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl,

wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl and heteroarylalkyl for R³ and theheterocyclyl moieties whose structures are shown immediately above forR³ can be unsubstituted or optionally independently substituted with oneor more moieties which can be the same or different, each moiety beingindependently selected from the group consisting of halogen, alkyl,aryl, cycloalkyl, CF₃, CN, —OCF₃, —(CR⁴R⁵)_(p)OR⁵, —OR⁵, —NR⁵R⁶,—(CR⁴R⁵)_(p)NR⁵R⁶, —C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R⁶, —SR⁶, —S(O₂)R⁶,—S(O₂)NR⁵R⁶, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷, —N(R⁵)C(R⁴R⁵)_(n)N(R⁵R⁶) and—N(R⁵)C(O)NR⁵R⁶, with the proviso that no carbon adjacent to a nitrogenatom on a heterocyclyl ring carries a —OR⁵ moiety;

R⁴ is H, halo or alkyl;

R⁵ is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl;

R⁶ is selected from the group consisting of H, Boc, alkyl, alkenyl,aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of saidalkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, and heteroarylalkyl can be unsubstituted or optionallysubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from the groupconsisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF₃,OCF₃, CN, —OR⁵, —NR⁵R¹⁰, —C(R⁴R⁵)_(p)—R⁹, —N(R⁵)Boc, —(CR⁴R⁵)_(p)OR⁵,—C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R¹⁰, —SO₃H, —SR¹⁰, —S(O₂)R⁷, —S(O₂)NR⁵R¹⁰,—N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R¹⁰;

R¹⁰ is selected from the group consisting of H, alkyl, aryl, arylalkyl,cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, andheteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl,cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, andheteroarylalkyl can be unsubstituted or optionally substituted with oneor more moieties which can be the same or different, each moiety beingindependently selected from the group consisting of halogen, alkyl,aryl, cycloalkyl, heterocyclylalkyl, CF₃, OCF₃, CN, —OR⁵, —NR⁴R⁵,—C(R⁴R⁵)_(p)—R⁹, —N(R⁵)Boc, —(CR⁴R⁵)_(p)OR⁵, —C(O₂)R⁵, —C(O)NR⁴R⁵,—C(O)R⁵, —SO₃H, —SR⁵, —S(O₂)R⁷, —S(O₂)NR⁴R⁵, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷and —N(R⁵)C(O)NR⁴R⁵;

or optionally (i) R⁵ and R¹⁰ in the moiety —NR⁵R¹⁰, or (ii) R⁵ and R⁶ inthe moiety —NR⁵R⁶, may be joined together to form a cycloalkyl orheterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moietybeing unsubstituted or optionally independently being substituted withone or more R⁹ groups;

R⁷ is selected from the group consisting of alkyl, cycloalkyl, aryl,arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl,and heterocyclyl, wherein each of said alkyl, cycloalkyl,heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted oroptionally independently substituted with one or more moieties which canbe the same or different, each moiety being independently selected fromthe group consisting of halogen, alkyl, aryl, cycloalkyl, CF₃, OCF₃, CN,—OR⁵, —NR⁵R¹⁰, —CH₂OR⁵, —C(O₂)R⁵, —C(O)NR⁵R¹⁰, —C(O)R⁵, —SR¹⁰,—S(O₂)R¹⁰, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R¹⁰, —N(R⁵)C(O)R¹⁰ and—N(R⁵)C(O)NR⁵R¹⁰;

R⁸ is selected from the group consisting of R⁶, —OR⁶, —C(O)NR⁵R¹⁰,—S(O₂)NR⁵R¹⁰, —C(O)R⁷, —C(═N—CN)—NH₂, —C(═NH)—NHR⁵, heterocyclyl, and—S(O₂)R⁷;

R⁹ is selected from the group consisting of halogen, —CN, —NR⁵R¹⁰, —SCN,—NO₂, —C(O)R⁵, —C(O₂)R⁶, —C(O)NR⁵R¹⁰, —OR⁶, —SR⁶, —S(O₂)R⁷,—S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R¹⁰;

m is 0 to 4;

n is 1 to 4; and

p is 1 to 4,with the proviso that when R² is phenyl, R³ is not alkyl, alkynyl orhalogen, and that when R² is aryl, R is not

and with the further proviso that when R is arylalkyl, then anyheteroaryl substituent on the aryl of said arylalkyl contains at leastthree heteroatoms.

The compounds of Formula III can be useful as protein kinase inhibitorsand can be useful in the treatment and prevention of proliferativediseases, for example, cancer, inflammation and arthritis. They may alsobe useful in the treatment of neurodegenerative diseases suchAlzheimer's disease, cardiovascular diseases, viral diseases and fungaldiseases.

DETAILED DESCRIPTION

In one embodiment, the present invention disclosespyrazolo[1,5-a]pyrimidine compounds which are represented by structuralFormula III, or a pharmaceutically acceptable salt or solvate thereof,wherein the various moieties are as described above.

In another embodiment, R is —(CHR⁵)_(n)-aryl, —(CHR⁵)_(n)-heteroaryl,—(CHR⁵)_(n)-heteroaryl (with said heteroaryl being substituted with anadditional, same or different, heteroaryl), —(CHR⁵)_(n)-heterocyclyl(with said heterocyclyl being substituted with an additional, same ordifferent, heterocyclyl), or

In another embodiment, R² is halogen, CF₃, CN, lower alkyl, alkylsubstituted with —OR⁶, alkynyl, aryl, heteroaryl or heterocyclyl.

In another embodiment, R³ is H, lower alkyl, aryl, heteroaryl,cycloalkyl, —NR⁵R⁶,

wherein said alkyl, aryl, heteroaryl, cycloalkyl and the heterocyclylstructures shown immediately above for R³ are optionally substitutedwith one or more moieties which can be the same or different, eachmoiety being independently selected from the group consisting ofhalogen, CF₃, OCF₃, lower alkyl, CN, —C(O)R⁵, —S(O₂)R⁵, —C(═NH)—NH₂,—C(═CN)—NH₂, hydroxyalkyl, alkoxycarbonyl, —SR⁵, and OR⁵, with theproviso that no carbon adjacent to a nitrogen atom on a heterocyclylring carries a —OR⁵ moiety.

In another embodiment, R⁴ is H or lower alkyl.

In another embodiment, R⁵ is H, lower alkyl or cycloalkyl.

In another embodiment, n is 1 to 2.

In an additional embodiment, R is —(CHR⁵)_(n)-aryl,—(CHR⁵)_(n)-heteroaryl.

In an additional embodiment, R² is halogen, CF₃, CN, lower alkyl,alkynyl, or alkyl substituted with —OR⁶.

In an additional embodiment, R² is lower alkyl, alkynyl or Br.

In an additional embodiment, R³ is H, lower alkyl, aryl,

wherein said alkyl, aryl and the heterocyclyl moieties shown immediatelyabove for R³ are optionally substituted with one or more moieties whichcan be the same or different, each moiety being independently selectedfrom the group consisting of halogen, CF₃, lower alkyl, hydroxyalkyl,alkoxy, —S(O₂)R⁵, and CN.

In an additional embodiment, R⁴ is H.

In an additional embodiment, R⁵ is H, ethyl, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

In an additional embodiment, R⁸ is alkyl or hydroxyalkyl.

In an additional embodiment, n is 1.

In an additional embodiment, p is 1 or 2.

In another embodiment, R is H.

In another embodiment, R² is halogen.

In another embodiment, R² is thiophene, furan, pyridine, pyrazole,alkylthio or arylthio, wherein each of said alkyl and aryl of R² canindependently be unsubstituted or substituted as defined above.

In another embodiment, R² is thiophene, furan, pyridine or pyrazole.

In another embodiment, R² is an amide which can be unsubstituted orsubstituted as defined above.

In another embodiment, R² is an urea, which may be unsubstituted orsubstituted as defined above.

In another embodiment, R² is an alkenyl.

In another embodiment, R² is an alkynyl.

In another embodiment, R3 is —NR⁵R⁶.

In another embodiment, R⁴ is H.

In another embodiment, R⁴ is unsubstituted lower alkyl.

In another embodiment, R⁴ is alkyl substituted with —OR⁶.

In another embodiment, R⁴ is halo.

In another embodiment, R⁴ is —F, —CI or —Br.

In another embodiment, both R² and R⁴ are halogen.

In another embodiment, both R² and R⁴ are halo and R is H.

In another embodiment, R is H, R² is halo and R³ is heteroaryl.

In another embodiment, R is H, R² is halo and R³ is aryl.

In another embodiment, R is H, R² is halo and R³ is heterocyclyl.

Another embodiment discloses the inventive compounds shown in Table 1,which exhibited CDK2 inhibitory activity of about 0.0001 μM to >about 5μM. The assay methods are described later (from page 333 onwards). TABLE1

Another embodiment of the invention discloses the following compounds,which exhibited CDK2 inhibitory activity of about 0.0001 μM to about 0.1μM:

Still additionally disclosed are the following compounds:

or a pharmaceutically acceptable salt or solvate thereof.

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. “Alkyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl),—N(alkyl)₂, carboxy and —C(O)O-alkyl. Non-limiting examples of suitablealkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. “Alkenyl” may be unsubstituted or optionally substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl. aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. “Alkynyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of alkyl, aryl and cycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. Non-limitingexamples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, pyridone (including N-substituted pyridones),isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

“Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryland alkyl are as previously described. Preferred aralkyls comprise alower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl. The bond to theparent moiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Preferred alkylaryls comprise a lower alkylgroup. Non-limiting example of a suitable alkylaryl group is tolyl. Thebond to the parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyland the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike. Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable cycloalkenylalkyls include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl,heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl),Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NSO₂— and —SO₂NY₁Y₂, wherein Y₁and Y₂ can be the same or different and are independently selected fromthe group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl.“Ring system substituent” may also mean a single moiety whichsimultaneously replaces two available hydrogens on two adjacent carbonatoms (one H on each carbon) on a ring system. Examples of such moietyare methylene dioxy, ethylenedioxy, —C(CH₃)₂— and the like which formmoieties such as, for example:

“Heteroarylalkyl” means a heteroaryl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to about 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclyls containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. Any —NH in a heterocyclylring may exist protected such as, for example, as an —N(Boc), —N(CBz),—N(Tos) group and the like; such protections are also considered part ofthis invention. The heterocyclyl can be optionally substituted by one ormore “ring system substituents” which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, lactam, lactone, and the like. “Heterocyclyl” mayalso mean a single moiety (e.g., carbonyl) which simultaneously replacestwo available hydrogens on the same carbon atom on a ring system.Example of such moiety is pyrrolidone:

“Heterocyclylalkyl” means a heterocyclyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable heterocyclylalkyls include piperidinylmethyl,piperazinylmethyl and the like.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising about 3 to about 10 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur atom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.The prefix aza, oxa or thia before the heterocyclenyl root name meansthat at least a nitrogen, oxygen or sulfur atom respectively is presentas a ring atom. The heterocyclenyl can be optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined above. The nitrogen or sulfur atom of the heterocyclenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable heterocyclenyl groupsinclude 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl,1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl”may also mean a single moiety (e.g., carbonyl) which simultaneouslyreplaces two available hydrogens on the same carbon atom on a ringsystem. Example of such moiety is pyrrolidinone:

“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined abovelinked via an alkyl moiety (defined above) to a parent core.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process or natural source or combinationthereof. Thus, the term “purified”, “in purified form” or “in isolatedand purified form” for a compound refers to the physical state of saidcompound after being obtained from a purification process or processesdescribed herein or well known to the skilled artisan, in sufficientpurity to be characterizable by standard analytical techniques describedherein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula III, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of Formula(III) or a pharmaceutically acceptable salt, hydrate or solvate of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of Formula (III) or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula (III) contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula (III) incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N- ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS Pharm Sci Tech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula III can form salts which are also within thescope of this invention. Reference to a compound of Formula III hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula III contains both a basic moiety, such as, but not limited toa pyridine or imidazole, and an acidic moiety, such as, but not limitedto a carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula III may be formed, for example, by reacting a compound ofFormula III with an amount of acid or base, such as an equivalentamount, in a medium such as one in which the salt precipitates or in anaqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di(C₆₋₂₄)acyl glycerol.

Compounds of Formula III, and salts, solvates, esters and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention.

The compounds of Formula (III) may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of Formula (III) as wellas mixtures thereof, including racemic mixtures, form part of thepresent invention. In addition, the present invention embraces allgeometric and positional isomers. For example, if a compound of Formula(III) incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula (III) may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula (III) may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula (III) incorporates a double bond or a fusedring, both the cis- and trans-forms, as well as mixtures, are embracedwithin the scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.)Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of Formula (III) (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of Formula (III) cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

Polymorphic forms of the compounds of Formula III, and of the salts,solvates, esters and prodrugs of the compounds of Formula III, areintended to be included in the present invention.

The term “pharmaceutical composition” is also intended to encompass boththe bulk composition and individual dosage units comprised of more thanone (e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the afore-said “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like. Similarly, the herein-described method of treating apatient by administering a pharmaceutical composition of the presentinvention is also intended to encompass the administration of theafore-said bulk composition and individual dosage units.

The compounds according to the invention have pharmacologicalproperties; in particular, the compounds of Formula III can beinhibitors of protein kinases such as, for example, the inhibitors ofthe cyclin-dependent kinases, mitogen-activated protein kinase(MAPK/ERK), glycogen synthase kinase 3(GSK3beta) and the like. Thecyclin dependent kinases (CDKs) include, for example, CDC2 (CDK1), CDK2,CDK4, CDK5, CDK6, CDK7 CDK8 and CDK9. The novel compounds of Formula IIIare expected to be useful in the therapy of proliferative diseases suchas cancer, autoimmune diseases, viral diseases, fungal diseases,neurological/neurodegenerative disorders, arthritis, inflammation,anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia andcardiovascular disease. Many of these diseases and disorders are listedin U.S. Pat. No. 6,413,974 cited earlier, the disclosure of which isincorporated herein.

More specifically, the compounds of Formula III can be useful in thetreatment of a variety of cancers, including (but not limited to) thefollowing: carcinoma, including that of the bladder, breast, colon,kidney, liver, lung, including small cell lung cancer, non-small celllung cancer, head and neck, esophagus, gall bladder, ovary, pancreas,stomach, cervix, thyroid, prostate, and skin, including squamous cellcarcinoma;

hematopoietic tumors of lymphoid lineage, including leukemia, acutelymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma,T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy celllymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma;

hematopoietic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia;

tumors of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma;

tumors of the central and peripheral nervous system, includingastrocytoma, neuroblastoma, glioma and schwannomas; and

other tumors, including melanoma, seminoma, teratocarcinoma,osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroidfollicular cancer and Kaposi's sarcoma.

Non-limiting examples of some specific diseases that can be treatedusing the compounds and/or pharmaceutical compositions comprising suchcompounds, and/or with combination anti-cancer agents include thefollowing:

tumor of the bladder, breast (including BRCA-mutated breast cancer),colorectal, colon, kidney, liver, lung, small cell lung cancer,non-small cell lung cancer, head and neck, esophagus, bladder, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin,including squamous cell carcinoma;

leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia,B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkinslymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma andBurkett's lymphoma;

chronic lymphocytic leukemia (“CLL”),

acute and chronic myelogenous leukemia, myelodysplastic syndrome andpromyelocytic leukemia;

fibrosarcoma, rhabdomyosarcoma;

head and neck, mantle cell lymphoma, myeloma;

astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glialtumors, astrocytoma, hepatocellular carcinoma, gastrointestinal stromaltumors (“GIST”) and schwannomas;

melanoma, multiple myeloma, seminoma, teratocarcinoma, osteosarcoma,xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer andKaposi's sarcoma.

Due to the key role of CDKs in the regulation of cellular proliferationin general, inhibitors could act as reversible cytostatic agents whichmay be useful in the treatment of any disease process which featuresabnormal cellular proliferation, e.g., benign prostate hyperplasia,familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis,pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosisfollowing angioplasty or vascular surgery, hypertrophic scar formation,inflammatory bowel disease, transplantation rejection, endotoxic shock,and fungal infections.

Compounds of Formula III may also be useful in the treatment ofAlzheimer's disease, as suggested by the recent finding that CDK5 isinvolved in the phosphorylation of tau protein (J. Biochem, (1995) 117,741-749).

Compounds of Formula III may induce or inhibit apoptosis. The apoptoticresponse is aberrant in a variety of human diseases. Compounds ofFormula III, as modulators of apoptosis, will be useful in the treatmentof cancer (including but not limited to those types mentionedhereinabove), viral infections (including but not limited to herpevirus,poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), preventionof AIDS development in HIV-infected individuals, autoimmune diseases(including but not limited to systemic lupus, erythematosus, autoimmunemediated glomerulonephritis, rheumatoid arthritis, psoriasis,inflammatory bowel disease, and autoimmune diabetes mellitus),neurodegenerative disorders (including but not limited to Alzheimer'sdisease, AIDS-related dementia, Parkinson's disease, amyotrophic lateralsclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellardegeneration), myelodysplastic syndromes, aplastic anemia, ischemicinjury associated with myocardial infarctions, stroke and reperfusioninjury, arrhythmia, atherosclerosis, toxin-induced or alcohol relatedliver diseases, hematological diseases (including but not limited tochronic anemia and aplastic anemia), degenerative diseases of themusculoskeletal system (including but not limited to osteoporosis andarthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiplesclerosis, kidney diseases and cancer pain.

Compounds of Formula III, as inhibitors of the CDKs, can modulate thelevel of cellular RNA and DNA synthesis. These agents would therefore beuseful in the treatment of viral infections (including but not limitedto HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barrvirus, Sindbis virus and adenovirus).

Compounds of Formula III may also be useful in the chemoprevention ofcancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by either blocking the initiating mutagenic event or byblocking the progression of pre-malignant cells that have alreadysuffered an insult or inhibiting tumor relapse.

Compounds of Formula III may also be useful in inhibiting tumorangiogenesis and metastasis.

Compounds of Formula III may also act as inhibitors of other proteinkinases, e.g., protein kinase C, her2, raf 1, MEK1, MAP kinase, EGFreceptor, PDGF receptor, IGF receptor, PI3 kinase, wee1 kinase, Src, Abland thus be effective in the treatment of diseases associated with otherprotein kinases.

Another aspect of this invention is a method of treating a mammal (e.g.,human) having a disease or condition associated with the CDKs byadministering a therapeutically effective amount of at least onecompound of Formula III, or a pharmaceutically acceptable salt orsolvate of said compound to the mammal.

A preferred dosage is about 0.001 to 500 mg/kg of body weight/day of thecompound of Formula III. An especially preferred dosage is about 0.01 to25 mg/kg of body weight/day of a compound of Formula III, or apharmaceutically acceptable salt or solvate of said compound.

The compounds of this invention may also be useful in combination(administered together or sequentially) with one or more of anti-cancertreatments such as radiation therapy, and/or one or more anti-canceragents selected from the group consisting of cytostatic agents,cytotoxic agents (such as for example, but not limited to, DNAinteractive agents (such as cisplatin or doxorubicin)); taxanes (e.g.taxotere, taxol); topoisomerase II inhibitors (such as etoposide);topoisomerase I inhibitors (such as irinotecan (or CPT-11), camptostar,or topotecan); tubulin interacting agents (such as paclitaxel, docetaxelor the epothilones); hormonal agents (such as tamoxifen); thymidilatesynthase inhibitors (such as 5-fluorouracil); anti-metabolites (such asmethoxtrexate); alkylating agents (such as temozolomide (TEMODAR™ fromSchering-Plough Corporation, Kenilworth, N.J.), cyclophosphamide);Farnesyl protein transferase inhibitors (such as, SARASAR™(4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxamide,or SCH 66336 from Schering-Plough Corporation, Kenilworth, N.J.),tipifarnib (Zarnestra® or R115777 from Janssen Pharmaceuticals),L778,123 (a farnesyl protein transferase inhibitor from Merck & Company,Whitehouse Station, N.J.), BMS 214662 (a farnesyl protein transferaseinhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, N.J.);signal transduction inhibitors (such as, Iressa (from Astra ZenecaPharmaceuticals, England), Tarceva (EGFR kinase inhibitors), antibodiesto EGFR (e.g., C225), GLEEVEC™ (C-abl kinase inhibitor from NovartisPharmaceuticals, East Hanover, N.J.); interferons such as, for example,intron (from Schering-Plough Corporation), Peg-Intron (fromSchering-Plough Corporation); hormonal therapy combinations; aromatasecombinations; ara-C, adriamycin, cytoxan, and gemcitabine.

Other anti-cancer (also known as anti-neoplastic) agents include but arenot limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan,Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,oxaliplatin (ELOXATIN™ from Sanofi-Synthelabo Pharmaeuticals, France),Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, liposomal doxorubicin (e.g.,Caelyx®, Myocet®, Doxil®), Epirubicin, Idarubicin, Mithramycin,Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Fulvestrant, Ifosfomide, Rituximab, C225 (or Cetuximab from Merck KGaA,Darmstadt, Germany), and Campath.

The compounds of this invention may specifically be useful incombination (administered together, concurrently or sequentially) withat least one compound selected from the group consisting of a cytostaticagent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan,camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen,5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH66336, R11577®, L778,123®, BMS 214662®, Iressa®, Tarceva®, antibodies toEGFR, antibodies to IGFR (including, for example, those published in US2005/0136063 published Jun. 23, 2005), KSP inhibitors (such as, forexample, those published in WO 2006/098962 and WO 2006/098961;ispinesib, SB-743921 from Cytokinetics), centrosome associated protein E(“CENP-E”) inhibitors (e.g., GSK-923295), Gleevec®, intron, ara-C,adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine,Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, bortezomib (“Velcade”),Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal,Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant,Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225®, satriplatin,Alimta® (pemetrexed), Mylotarg® (Gemtuzumab ozogamicin), Avastin®(bevacizumab), panitubimab, Sutent® (sunitinib), sorafenib, Sprycel®(dastinib), nilotinib, Tykerb® (lapatinib) and Campath. This mayoptionally be combined with radiation therapy.

The compounds of this invention may specifically be useful incombination (administered together, concurrently or sequentially) withtemozolomide and/or radiation therapy.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically active agent or treatment within its dosagerange. For example, the CDC2 inhibitor olomucine has been found to actsynergistically with known cytotoxic agents in inducing apoptosis (J.Cell Sci., (1995) 108, 2897. Compounds of Formula III may also beadministered sequentially with known anticancer or cytotoxic agents whena combination formulation is inappropriate. The invention is not limitedin the sequence of administration; compounds of Formula III may beadministered either prior to or after administration of the knownanticancer or cytotoxic agent. For example, the cytotoxic activity ofthe cyclin-dependent kinase inhibitor flavopiridol is affected by thesequence of administration with anticancer agents. Cancer Research,(1997) 57, 3375. Such techniques are within the skills of personsskilled in the art as well as attending physicians.

Accordingly, in an aspect, this invention includes combinationscomprising an amount of at least one compound of Formula III, or apharmaceutically acceptable salt or solvate thereof, and an amount ofone or more anti-cancer treatments and anti-cancer agents listed abovewherein the amounts of the compounds/treatments result in desiredtherapeutic effect.

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The exemplifiedpharmacological assays which are described later have been carried outwith the compounds according to the invention and their salts.

This invention is also directed to pharmaceutical compositions whichcomprise at least one compound of Formula III, or a pharmaceuticallyacceptable salt or solvate of said compound and at least onepharmaceutically acceptable carrier.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally or intravenously.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two tofour divided doses.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of at least one compound of Formula III, or apharmaceutically acceptable salt or solvate of said compound and apharmaceutically acceptable carrier, vehicle or diluent.

Yet another aspect of this invention is a kit comprising an amount of atleast one compound of Formula III, or a pharmaceutically acceptable saltor solvate of said compound and an amount of at least one anticancertherapy and/or anti-cancer agent listed above, wherein the amounts ofthe two or more ingredients result in desired therapeutic effect.

The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures will be apparent to those skilled in the art.

Where NMR data are presented, ¹H spectra were obtained on either aVarian VXR-200 (200 MHz, ¹H), Varian Gemini-300 (300 MHz) or XL-400 (400MHz) and are reported as ppm down field from Me₄Si with number ofprotons, multiplicities, and coupling constants in Hertz indicatedparenthetically. Where LC/MS data are presented, analyses was performedusing an Applied Biosystems API-100 mass spectrometer and ShimadzuSCL-10A LC column: Altech platinum C18, 3 micron, 33 mm×7 mm ID;gradient flow: 0 min—10% CH₃CN, 5 min—95% CH₃CN, 7 min—95% CH₃CN, 7.5min—10% CH₃CN, 9 min—stop. The retention time and observed parent ionare given.

The following solvents and reagents may be referred to by theirabbreviations in parenthesis:

Thin layer chromatography: TLC

dichloromethane: CH₂Cl₂

ethyl acetate: AcOEt or EtOAc

methanol: MeOH

trifluoroacetate: TFA

triethylamine: Et₃N or TEA

butoxycarbonyl: n-Boc or Boc

nuclear magnetic resonance spectroscopy: NMR

liquid chromatography mass spectrometry: LCMS

high resolution mass spectrometry: HRMS

milliliters: mL

millimoles: mmol

microliters: μl

grams: g

milligrams: mg

room temperature or rt (ambient): about 25° C.

dimethoxyethane: DME

EXAMPLES

In general, the compounds described in this invention can be preparedthrough the general routes described below in Scheme 1. Treatment of the

starting nitrile with potassium t-butoxide and ethyl formate gives riseto the intermediate enol 2 which upon treatment with hydrazine gives thedesired substituted 3-aminopyrazole. Condensation of compounds of type 3with the appropriately functionalized keto ester of type 5 gives rise tothe pyridones 6 as shown in Scheme 3. The keto esters used in thisgeneral route are either commercially available or can be made asillustrated in Scheme 2.

The chlorides of type 9 can be prepared by treatment of the pyridones 8with POCl₃. When R² is equal to H, substitution in this position ispossible on the compounds of type 9 by electrophilic halogenation,acylation, and various other electrophilic aromatic substitutions.

Introduction of the N7-amino functionality can be accomplished throughdisplacement of the chloride of compounds of type 9 by reaction with theappropriate amine as shown in Scheme 3.

Condensation of compounds of type 7 with the appropriatelyfunctionalized malonate ester of type 11 gives rise to the pyridones 13as shown in Scheme 4.

The chlorides of type 14 can be prepared by treatment of the pyridones13 with POCl₃. When R² is H, substitution in this position is possibleon compounds of type 9 by electrophilic halogenation, acylation, andvarious other electrophilic aromatic substitutions.

Incorporation of the N7-amino functionality can be accomplished throughregioselective displacement of the chloride of compounds of type 14.Incorporation of the N5-amino functionality by addition of anappropriate amine at higher temperature.

Alternatively, condensations of the aminopyrazoles of type 7 with anappropriately functionalize keto ester as prepared in Scheme 5, leads tocompounds of type 13 as shown in Scheme 4.

The chlorides of type 14 can be prepared by treatment of the pyridones13 with POCl₃. When R² is equal to H, substitution in this position ispossible on compounds of type 14 by electrophilic halogenation,acylation, and various other electrophilic aromatic substitutions.

Incorporation of the N7-amino functionality can be accomplished throughdisplacement of the chloride of compounds of type 15.

PREPARATIVE EXAMPLES Preparative Example 1

A procedure in German patent DE 19834047 A1, p 19 was followed. To asolution of KOtBu (6.17 g, 0.055 mol) in anhydrous THF (40 mL) wasadded, dropwise, a solution of cyclopropylacetonitrile (2.0 g, 0.025mol) and ethyl formate (4.07 g, 0.055 mol) in anhydrous THF (4 mL). Aprecipitate formed immediately. This mixture was stirred for 12 hr. Itwas concentrated under vacuum and the residue stirred with Et₂O (50 mL).The resulting residue was decanted and washed with Et₂O (2×50 mL) andEt₂O removed from the residue under vacuum. The residue was dissolved incold H₂O (20 mL) and pH adjusted to 4-5 with 12 N HCl. The mixture wasextracted with CH₂Cl₂ (2×50 mL). The organic layers were combined, driedover MgSO₄ and concentrated under vacuum to give the aldehyde as a tanliquid.Step B:

The product from Preparative Example 1, Step A (2.12 g, 0.0195 mol),NH₂NH₂.H₂O (1.95 g, 0.039 mol) and 1.8 g (0.029 mole) of glacial CH₃CO₂H(1.8 g, 0.029 mol) were dissolved in EtOH (10 mL). It was refluxed for 6hr and concentrated under vacuum. The residue was slurried in CH₂Cl₂(150 mL) and the pH adjusted to 9 with 1N NaOH. The organic layer washedwith brine, dried over MgSO₄ and concentrated under vacuum to give theproduct as a waxy orange solid.

Preparative Examples 2-4

By essentially the same procedure set forth in Preparative Example 1,only substituting the nitrile shown in Column 2 of Table 2, thecompounds in Column 3 of Table 2 were prepared: TABLE 2 Prep. Ex. Column2 Column 3 2

3

3.10

Preparative Example 4

2-Carbomethoxycyclopentanone (6.6 ml, 0.05 mol) in THF (15 ml) was addeddropwise to a vigorously stirred suspension of NaH (60% in mineral oil,4 g, 0.1 mol) in THF (100 ml) at 0-10° C. When bubbling ceased, thereaction mixture was treated at the same temperature with ClCOOMe (7.8ml, 0.1 mol) in THF (15 ml). The resulted off-white suspension wasstirred for 30 minutes at room temperature and 30 minutes under reflux.The reaction was monitored by TLC for disappearance of startingmaterial. The reaction mixture was quenched with water carefully andpartitioned between ethyl acetate and saturated solution of ammoniumchloride in a funnel. Shaken and separated, the organic layer was washedwith brine and dried over anhydrous sodium sulfate. Solvents wereremoved, and the residue was purified by flash chromatography, elutedwith 5% and then 10% ethyl acetate in hexane. 9.4 g colorless oil wasobtained with 94% yield. ¹H NMR (CDCl₃) δ 3.90 (s, 3H), 3.73 (s, 3H),2.65 (m, 4H), 1.98 (m, 2H).

Preparative Example 5

To lithium diisopropylamide solution in THF (2.0 N, 0.04 mol) at −65°C., was added dropwise 2,2-dicarbomethoxycyclopentanone (4 g, 0.02 mol)in THF (60 ml). The resulted reaction mixture was stirred at the sametemperature before adding methyl chloroformate (1.54 ml, 0.02 mol).Reaction mixture stirred for an hour and poured into saturated ammoniumchloride solution with some ice. This solution was extracted three timeswith ether, and the combined ethereal layers were dried over sodiumsulfate. Solvents were removed in vacuo, and the residue was purified byflash chromatography, eluted with 30% increased to 50% ethyl acetate inhexane. 2.3 g yellowish oil was obtained with 58% yield. ¹H NMR (CDCl₃)δ 3.77 (s, 6H), 3.32 (t, 1H), 3.60-3.10 (m, 4H).

Preparative Example 6

The reactions were done as outlined in (K. O. Olsen, J. Org. Chem.,(1987) 52, 4531-4536). Thus, to a stirred solution of lithiumdiisopropylamide in THF at −65 to −70 C was added freshly distilledethyl acetate, dropwise. The resulting solution was stirred for 30 minand the acid chloride was added as a solution in THF. The reactionmixture was stirred at −65 to −70° C. for 30 min and then terminated bythe addition of 1 N HCl solution. The resulting two-phased mixture wasallowed to warm to ambient temperature. The resulting mixture wasdiluted with EtOAc (100 mL) the organic layer was collected. The aqueouslayer was extracted with EtOAc (100 mL). The organic layers werecombined, washed with brine, dried (Na₂SO₄), and concentrated in vacuoto give the crude β-keto esters, which were used in the subsequentcondensations.

Preparative Examples 7-19

By essentially the same procedure set forth in Preparative Example 6only substituting the acid chlorides shown in Column 2 of Table 3, theβ-keto esters shown in Column 3 of Table 3 were prepared: TABLE 3 Prep.Ex. Column 2 Column 3 DATA 7

LCMS: MH⁺ = 223 8

LCMS: MH⁺ = 253 9

LCMS: MH⁺ = 261 10

MH⁺ = 199 11

12

13

LCMS: MH⁺ = 271 14

Yield = quant MH⁺ = 249 15

Yield = quant MH⁺ = 237 16

Yield = quant MH⁺ = 262 17

Yield = 48 MH⁺ = 195 18

Yield = 99 MH⁺ = 199 19

Yield = 77% ¹H NMR (CDCl₃) δ 7.42 (t, 1H), 6.68 (d, 2H), 4.29 (q, 2H),3.97 (d, 2H), 3.95 (s, 3H), 1.38 (t, 3H).

Preparative Example 20

To a solution of the acid in THF was added Et₃N, followed by isobutylchloroformate at −20 to −30° C. After the mixture was stirred for 30 minat −20 to −30° C., triethylamine hydrochloride was filtered off underargon, and the filtrate was added to the LDA-EtOAc reaction mixture(prepared as outlined in Method A) at −65 to −70° C. After addition of 1N HCl, followed by routine workup of the reaction mixture andevaporation of the solvents, the crude β-keto esters were isolated. Thecrude material was used in the subsequent condensations.

Preparative Examples 21-28

By essentially the same conditions set forth in Preparative Example 20only substituting the carboxylic acid shown in Column 2 of Table 4, thecompounds shown in Column 3 of Table 4 were prepared: TABLE 4 Prep. Ex.Column 2 Column 3 CMPD 21

Yield = 99% MH⁺ = 213 22

Yield = 70% MH⁺ = 275 23

Yield = quant MH⁺ = 213 24

Yield = quant MH⁺ = 211 25

Yield = 99 MH⁺ = 334 26

Yield = 99 MH⁺ = 334 27

Yield = 99 MH⁺ = 334 28

Yield = 77% ¹H NMR (CDCl₃) δ4.21 (q, 2H), 3.95 (d, 2H), 3.93-3.79 (m,4H), 3.52 (s, 2H), 2.65 (m, 1H), 1.25 (t, 3H), 1.23-1.2 (m, 2H).

Preparative Example 29

A solution of 3-aminopyrazole (2.0 g, 24.07 mmol) and ethylbenzoylacetate (4.58 mL, 1.1 eq.) in AcOH (15 mL) was heated at refluxfor 3 hours. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The resulting solid was diluted with EtOAc andfiltered to give a white solid (2.04 g, 40% yield).

Preparative Examples 30-73

By essentially the same procedure set forth in Preparative Example 29only substituting the aminopyrazole shown in Column 2 of Table 5 and theester shown in Column 3 of Table 5, the compounds shown in Column 4 ofTable 5 were prepared: TABLE 5 Prep. Ex. Column 2 Column 3 Column 4Column 5 30

31

32

33

34

35

36

37

37.10

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

Yield =68 MH⁺ =152 59

Yield =68 MH⁺ =268 60

Yield =63 MH⁺ =255 61

Yield =80 MH⁺ =280 62

Yield = 72 MH⁺ =214 63

Yield =51 MH⁺ =218 64

Yield =82 MH⁺ =218 65

Yield =39 MH⁺ =232 66

Yield =30 MH⁺ =230 67

Yield =80 MH⁺ =353 68

Yield =49 MH⁺ =353 69

Yield =42 MH⁺ =353 70

71

72

73

Preparative Example 74

Ethyl benzoylacetate (1.76 mL, 1.1 eq.) and 3-amino-4-cyanopyrazole (1.0g, 9.25 mmol) in AcOH (5.0 mL) and H₂O (10 mL) was heated at reflux 72hours. The resulting solution was cooled to room temperature,concentrated in vacuo, and diluted with EtOAc. The resulting precipitatewas filtered, washed with EtOAc, and dried in vacuo (0.47 g, 21% yield).

Preparative Example 75

A procedure in U.S. Pat. No. 3,907,799 was followed. Sodium (2.3 g, 2eq.) was added to EtOH (150 mL) portionwise. When the sodium wascompletely dissolved, 3-aminopyrazole (4.2 g, 0.05 mol) and diethylmalonate (8.7 g, 1.1 eq.) were added and the resulting solution heatedto reflux for 3 hours. The resulting suspension was cooled to roomtemperature and filtered. The filter cake washed with EtOH (100 mL) anddissolved in water (250 mL). The resulting solution was cooled in an icebath and the pH adjusted to 1-2 with concentrated HCl. The resultingsuspension was filtered, washed with water (100 mL) and dried undervacuum to give a white solid (4.75 g, 63% yield).

Preparative Examples 76-78

By essentially the same procedure set forth in Preparative Example 75only substituting the compound shown in Column 2 of Table 6, thecompounds shown in Column 3 of Table 6 are prepared: TABLE 6 Prep. Ex.Column 2 Column 3 76

77

78

Preparative Example 79

A solution of the compound prepared in Preparative Example 29 (1.0 g,4.73 mmol) in POCl₃ (5 mL) and pyridine (0.25 mL) was stirred at roomtemperature 3 days. The resulting slurry was diluted with Et₂O,filtered, and the solid residue washed with Et₂O. The combined Et₂Owashings were cooled to 0° C. and treated with ice. When the vigorousreaction ceased, the resulting mixture was diluted with H₂O, separated,and the aqueous layer extracted with Et₂O. The combined organics werewashed with H₂O and saturated NaCl, dried over Na₂SO₄, filtered, andconcentrated to give a pale yellow solid (0.86 g, 79% yield). LCMS:MH⁺=230.

Preparative Example 80-122

By essentially the same procedure set forth in Preparative Example 79,only substituting the compound shown in Column 2 of Table 7, thecompounds shown in Column 3 of Table 7 were prepared: TABLE 7 Prep. Ex.Column 2 Column 3 CMPD 80

MS: MH⁺ = 248 81

82

MS: MH⁺ = 298 83

MS: MH⁺ = 196 84

MS: MH⁺ = 210 85

86

MS: MH⁺ = 272 87

87.10

88

MS: MH⁺ = 255 89

90

Yield = 65% MS: MH⁺ = 260 91

Yield = 35% MS: MH⁺ = 290 92

Yield = 32% MS: MH⁺ = 298 93

Yield = 45% MS: MH⁺ = 236 94

Yield = 100% LCMS: MH⁺ =250 95

Yield = 88% MS: MH⁺ = 314 96

Yield = 43% MS: MH⁺ = 223 97

Yield = 30% MS: MH⁺ = 295 98

Yield = 98% MS: MH⁺ = 244 99

100

101

102

103

104

105

106

107

45% yield; MS: MH⁺ = 226 108

MS: MH⁺ = 308 109

Yield = quant MH⁺ = 286 110

Yield = 50 MH⁺ = 272 111

Yield = 85 MH⁺ = 299 112

Yield = 97 MH⁺ = 231 113

Yield = 45 MH⁺ = 236 114

Yield = quant. MH⁺ = 236 115

Yield = 57 MH⁺ = 250 116

Yield = 89 MH⁺ = 248 117

Yield = 96 MH⁺ = 371 118

Yield = 99 MH⁺ = 371 119

Yield = 50 MH⁺ = 371 120

Yield = 57% LCMS: MH⁺ = 224 121

Yield = 34% LCMS: MH⁺ = 226 122

Yield = 100% ¹H NMR (CDCl₃) δ 8.53 (d, 1H), 7.66 (t, 1H), 7.51 (s, 1H),7.45 (d, 1H), 6.84 (d, 2H).

Preparative Example 123

POCl₃ (62 mL) was cooled to 5° C. under nitrogen and dimethylaniline(11.4 g, 2.8 eq.) and the compound prepared in Preparative Example 75(4.75 g, 0.032 mol). The reaction mixture was warmed to 60° C. andstirred overnight. The reaction mixture was cooled to 30° C. and thePOCl₃ was distilled off under reduced pressure. The residue wasdissolved in CH₂Cl₂ (300 mL) and poured onto ice. After stirring 15minutes, the pH of the mixture was adjusted to 7-8 with solid NaHCO₃.The layers were separated and the organic layer washed with H₂O (3×200mL), dried over MgSO₄, filtered, and concentrated. The crude product waspurified by flash chromatography using a 50:50 CH₂Cl₂:hexanes solutionas eluent to elute the dimethyl aniline. The eluent was then changed to75:25 CH₂Cl₂:hexanes to elute the desired product (4.58 g, 77% yield).MS: MH⁺=188.

Preparative Examples 124-126

By essentially the same procedure set forth in Preparative Example 123only substituting the compound in Column 2 of Table 8, the compoundsshown in Column 3 of Table 8 are prepared: TABLE 8 Prep. Ex. Column 2Column 3 124

125

126

Preparative Example 127

A solution of the compound prepared in Preparative Example 79 (0.10 g,0.435 mmol) in CH₃CN (3 mL) was treated with NBS (0.085 g, 1.1 eq.). Thereaction mixture was stirred at room temperature 1 hour and concentratedunder reduced pressure. The crude product was purified by flashchromatography using a 20% EtOAc-in-hexanes solution as eluent (0.13 g,100% yield). LCMS: MH⁺=308.

Preparative Examples 128-164

By essentially the same procedure set forth in Preparative Example 127only substituting the compounds shown in Column 2 of Table 9, thecompounds shown in Column 3 of Table 9 were prepared: TABLE 9 Prep. Ex.Column 2 Column 3 CMPD 128

MS: MH⁺ =326 129

MS: MH⁺ =342 130

MS: MH⁺ =376 131

MS: MH⁺ = 274 132

MS: MH⁺ = 288 133

134

Yield = 75% MS: MH⁺ =338 135

Yield = 52% MS: MH⁺ =368 136

Yield = 87% MS: MH⁺ =376 137

Yield = 100% MS: MH⁺ =316 138

Yield = 92% MS: MH⁺ =330 139

Yield = 82% MS: MH⁺ =395 140

Yield = 88% MS: MH⁺ = 308 141

Yield = 100% MS: MH⁺ = 322 142

MH⁺ = 266 143

144

145

146

147

148

149

150

151

LCMS: MH⁺ = 386 152

Yield = quant MH⁺ = 364 153

Yield = quant MH⁺ = 353 154

Yield = 95 MH⁺ = 378 155

Yield = 77 MH⁺ = 311 156

Yield = quant. MH⁺ = 314 157

Yield = 99 MH⁺ = 328 158

Yield = 98 MH⁺ = 326 159

Yield = 99 MH⁺ = 449 160

Yield = 95 MH⁺ = 449 161

Yield = 72 MH⁺ = 449 162

Yield = 98% LCMS: MH⁺ = 302 163

Yield = 95% LCMS: MH⁺ = 305 164

Yield = 50% ¹H NMR (CDCl₃) δ8.36 (s, 1H), 7.72 (d, 1H), 7.20 (s, 1H),6.82 (d, 1H), 3.99 (s, 3H), 3.90 (s, 3H);

Preparative Example 165

A solution of the compound prepared in Preparative Example 80 (0.3 g,1.2 mmol) in CH₃CN (15 mL) was treated with NCS (0.18 g, 1.1 eq.) andthe resulting solution heated to reflux 4 hours. Additional NCS (0.032g, 0.2 eq.) added and the resulting solution was stirred at refluxovernight. The reaction mixture was cooled to room temperature,concentrated in vacuo and the residue purified by flash chromatographyusing a 20% EtOAc in hexanes solution as eluent (0.28 g, 83% yield).LCMS: MH⁺=282.

Preparative Example 166-167

By essentially the same procedure set forth in Preparative Example 165only substituting the compound shown in Column 2 of Table 10, thecompound shown in Column 3 of Table 10 was prepared: TABLE 10 Prep. Ex.Column 2 Column 3 CMPD 166

Yield = 82% LCMS: MH⁺ =286 167

Preparative Example 167.10

By essentially the same procedure set forth in Preparative Example 165only substituting N-iodosuccinimide, the above compound was prepared.

Preparative Example 168

To a solution of the compound from Preparative Example 79 (1.0 g, 4.35mmol) in DMF (6 mL) was added POCl₃ (1.24 mL, 3.05 eq.) and theresulting mixture was stirred at room temperature overnight. Thereaction mixture was cooled to 0° C. and the excess POCl₃ was quenchedby the addition of ice. The resulting solution was neutralized with 1NNaOH, diluted with H₂O, and extracted with CH₂Cl₂. The combined organicswere dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography using a 5% MeOH in CH₂Cl₂solution as eluent (0.95 g, 85% yield). LCMS: MH⁺=258.

Preparative Example 169

By essentially the same procedure set forth in Preparative Example 168only substituting the compound prepared in Preparative Example 80, theabove compound was prepared (0.45 g, 40% yield).

Preparative Example 170

To a solution of the product of Preparative Example 169 (0.25 g, 0.97mmol) in THF was added NaBH₄ (0.041 g, 1.1 eq.) and the resultingsolution was stirred at room temperature overnight. The reaction mixturewas quenched by the addition of H₂O and extracted with CH₂Cl₂. Thecombined organics were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The crude product was purified by flashchromatography using a 60:40 hexanes:EtOAc mix as eluent (0.17 g, 69%yield). MS: MH⁺=260.

Preparative Example 171

A solution of the compound prepared in Preparative Example 170 (0.12 g,0.462 mmol), dimethyl sulfate (0.088 mL, 2.0 eq), 50% NaOH (0.26 mL) andcatalytic Bu₄NBr in CH₂Cl₂ (4 mL) was stirred at room temperatureovernight. The reaction mixture was diluted with H₂O and extracted withCH₂Cl₂. The combined organics were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude product was purified byflash chromatography using a 30% EtOAc-in-hexanes solution as eluent(0.062 g, 48% yield).

Preparative Example 172

To a solution of PPh₃ (4.07 g, 4.0 eq.) and CBr₄ (2.57 g, 2.0 eq.) inCH₂Cl₂ (75 mL) at 0° C. was added the compound prepared in PreparativeExample 168 (1.0 g, 3.88 mmol). The resulting solution was stirred at 0°C. for 1 hour and concentrated under reduced pressure. The residue waspurified by flash chromatography using a 20% EtOAc in hexanes solutionas eluent (1.07 g, 67% yield).

Preparative Example 173

By essentially the same procedure set forth in Preparative Example 172only substituting the compound prepared in Preparative Example 169 theabove compound was prepared (0.5 g, 70% yield).

Preparative Example 174

The compound prepared in Preparative Example 127 (3.08 g, 10.0 mmol),2.0 M NH₃ in 2-propanol (50 mL, 100.0 mmol), and 37% aqueous NH₃ (10.0mL) were stirred in a closed pressure vessel at 50° C. for 1 day. Thesolvent was evaporated and the crude product was purified by flashchromatography using 3:1 CH₂Cl₂:EtOAc as eluent. Pale yellow solid (2.30g, 80%) was obtained. LCMS: M⁺=289.

Preparative Examples 175-180

By essentially the same procedure set forth in Preparative Example 174only substituting the compound shown in Column 2 of Table 11, thecompounds shown in Column 3 of Table 11 were prepared. TABLE 11 Prep.Ex. Column 2 Column 3 175

176

177

178

179

180

Preparative Examples 181

The compound prepared in Preparative Example 80 (0.3 g, 1.2 mmol), K₂CO₃(0.33 g, 2 eq.), and 4-aminomethylpyridine (0.13 mL, 1.1 eq.) was heatedto reflux overnight. The reaction mixture was cooled to room temperatureand concentrated under reduced pressure. The residue was diluted withH₂O and extracted with CH₂Cl₂. The combined organics were dried overNa₂SO₄, filtered and, concentrated. The crude product was purified byflash chromatography using a 5% (10% NH₄OH in MeOH) solution in CH₂Cl₂as eluent (0.051 g, 40% yield). LCMS: MH⁺=320.

Preparative Example 182

By essentially the same procedure set forth in Preparative Example 181only substituting the compound described in Preparative Example 92, theabove compound was prepared. LCMS: MH⁺=370.

Preparative Example 183

To a solution of the compound prepared in Preparative Example 123 (0.25g, 1.3 mmol) in dioxane (5 mL) was added iPr₂NEt (0.47 mL, 2.0 eq.) and3-aminomethylpyridine (0.15 ml, 1.1 eq.). The resulting solution wasstirred at room temperature 72 hours. The reaction mixture was dilutedwith H₂O and extracted with EtOAc. The combined organics were washedwith H₂O and saturated NaCl, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by flashchromatography using a 5% MeOH in CH₂Cl₂ solution as eluent (0.29 g, 83%yield). MS: MH⁺=260.

Preparative Examples 184-187

By essentially the same procedure set forth in Preparative Example 183only substituting the compound shown in Column 2 of Table 12, thecompounds shown in Column 3 of Table 12 are prepared. TABLE 12 Prep. Ex.Column 2 Column 3 184

184.1

185

186

187

187.1

187.11

Preparative Example 188 and Preparative Example 189

To a solution of the compound prepared in Preparative Example 185 (1.18g, 3.98 mmol) in THF (35 mL) at −78° C. was added LAH (4.78 mL, 1M inEt₂O, 1.0 eq.) dropwise. The reaction mixture was stirred at −78° C. for3 hours at which time additional LAH (2.0 mL, 1M in Et₂O, 0.42 eq.) wasadded dropwise. The reaction mixture was stirred an additional 1.25hours and quenched by the addition of saturated Na₂SO₄ (8.5 mL). Thereaction mixture was diluted with EtOAC (23 mL), H₂O (2 mL), and CH₃OH(50 mL). The resulting slurry was filtered through a plug of Celite. TheCelite washed with CH₃OH and the filtrate dried with Na₂SO₄, filtered,and concentrated. The product was purified by flash chromatography usinga CH₂Cl₂:CH₃OH (93:7) solution as eluent to yield aldehyde as the firsteluting product and alcohol as the second eluting product.

Preparative Example 188

(aldehyde): 0.4 g, 39% yield. MS: MH⁺=254.

Preparative Example 189

(alcohol): 0.25 g, 24% yield. MS: MH⁺=256.

Preparative Example 190

To a solution of the compound prepared in Preparative Example 188 (0.075g, 0.30 mmol) in THF (2.0 mL) at 0° C. was added CH₃MgBr (0.3 mL, 3.0Msolution in Et₂O, 3.0 eq.) dropwise. The resulting solution was stirredat 0° C. an additional 1.5 hours, warmed to room temperature, andstirred overnight. Additional CH₃MgBr (0.15 mL, 3.0M in Et₂O, 1. eq.)was added and the resulting solution stirred an additional 1.5 hours.The reaction mixture was cooled to 0° C. and quenched by the addition ofsaturated NH₄Cl. The resulting solution was diluted with CH₂Cl₂ and H₂Oand extracted with CH₂Cl₂. The combined organics were washed withsaturated NaCl and dried over Na₂SO₄, filtered, and concentrated. Thecrude product was purified by flash chromatography using a CH₂Cl₂:CH₃OH(90:10) solution as eluent (0.048 g, 60% yield). MS: MH⁺=270.

Preparative Example 191

By essentially the same procedure set forth in Preparative Example 190only substituting the compound prepared in Preparative Example 185 andusing excess MeMgBr (5 eq.), the above compound was prepared.

Preparative Example 192

The compound prepared in Preparative Example 181 (0.29 g, 0.91 mmol),BOC₂O (0.22 g, 1.1 eq), and DMAP (0.13 g, 1.1 eq.) in dioxane (10 mL)was stirred at room temperature 3 days. Additional BOC₂O (0.10 g, 0.5eq.) was added and the reaction mixture was stirred 4 hours. Thereaction mixture was concentrated in vacuo, diluted with saturatedNaHCO₃ (15 mL), and extracted with CH₂Cl₂ (2×100 mL). The combinedorganics were dried over Na₂SO₄, filtered, and concentrated under reducepressure. The crude product was purified by flash chromatography using a5% (10% NH₄OH in MeOH) solution in CH₂Cl₂ as eluent (0.35 g, 91% yield).LCMS: MH⁺=420.

Preparative Example 193

By essentially the same procedure set forth in Preparative Example 192only substituting the compound prepared in Preparative Example 183, theabove compound was prepared. MS: MH⁺=360.

Preparative Example 193.10

By essentially the same procedure set forth in Preparative Example 192only substituting the compound prepared in Preparative Example 184.1,the above compound was prepared. MS: MH⁺=454.

Preparative Example 194

By essentially the same procedure set forth in Preparative Example 192only substituting the above compound prepared in Preparative Example187.11, the above compound was prepared (0.223 g, 88% yield). MS:MH⁺=528.

Preparative Example 195

By essentially the same procedure set forth in Preparative Example 127only substituting the compound prepared in Preparative Example 192, theabove compound was prepared (0.38 g, 95% yield). LCMS: MH⁺=498.

Preparative Example 196

By essentially the same procedure set forth in Preparative Example 195,only substituting the compound prepared in Preparative Example 193, theabove compound was prepared (0.3 g, 83% yield). MS: MH⁺=438.

Preparative Example 197

A solution of the compound prepared in Preparative Example 195 (0.15 g,0.3 mmol), phenylboronic acid (0.073 g, 2.0 eq.), K₃PO₄ (0.19 g, 3.0eq.), and Pd(PPh₃)₄ (0.017 g, 5 mol %) was heated at reflux in DME (16mL) and H₂O (4 mL) 7 hours. The resulting solution was cooled to roomtemperature, diluted with H₂O (10 mL), and extracted with CH₂Cl₂ (3×50mL). The combined organics were dried over Na₂SO₄, filtered, andconcentrated. The crude product was purified by flash chromatographyusing a 2.5% (10% NH₄OH in MeOH) in CH₂Cl₂ solution as eluent (0.16 g,100% yield).

Preparative Example 198

To a solution of 4-aminomethylpyridine (1.41 mL, 13.87 mmol) in CH₂Cl₂(50 mL) was added BOC₂O (3.3 g, 1.1 eq.) and TEA and the resultingsolution was stirred a room temperature 2 hours. The reaction mixturewas diluted with H₂O (50 mL) and extracted with CH₂Cl₂. The combinedorganics were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude product was purified by flash chromatography using a5% (10% NH₄OH in MeOH) solution in CH₂Cl₂ as eluent to give a yellowsolid (2.62 g, 91% yield). LCMS: MH⁺=209.

Preparative Example 199

By essentially the same procedure set forth in Preparative Example 198only substituting 3-aminomethylpyridine, the above compound was preparedas a yellow oil (2.66 g, 92% yield). LCMS: MH⁺=209.

Preparative Example 200

To a solution of the compound prepared in Preparative Example 198 (0.20g, 0.96 mmol) in CH₂Cl₂ (5 mL) at 0° C. was added MCPBA (0.17 g, 1.0 eq)and the resulting solution stirred at 0° C. 2 hours and stored at 4° C.overnight at which time the reaction mixture was warmed to roomtemperature and stirred 3 hours. The reaction mixture was diluted withH₂O and extracted with CH₂Cl₂. The combined organics were dried overNa₂SO₄, filtered, and concentrated. The crude product was purified byflash chromatography using a 10% (10% NH₄OH in MeOH) solution as eluent:LCMS: MH⁺=255.

Preparative Example 201

A solution of oxone (58.6 g) in H₂O (250 mL) was added dropwise to thecompound prepared in Preparative Example 199 (27 g, 0.13 mol) and NaHCO₃(21.8 g, 2.0 eq.) in MeOH (200 mL) and H₂O (250 mL). The resultingsolution was stirred at room temperature overnight. The reaction mixturewas diluted with CH₂Cl₂ (500 mL) and filtered. The layers were separatedand the aqueous layer extracted with CH₂Cl₂. The combined organics weredried over Na₂SO₄, filtered, and concentrated under reduced pressure togive a white solid (21.0 g, 72% yield). MS: MH⁺=255.

Preparative Example 202

The compound prepared in Preparative Example 200 (0.29 g, 1.29 mmol) wasstirred at room temperature in 4M HCl in dioxane (0.97 mL) 2 hours. Thereaction mixture was concentrated in vacuo and used without furtherpurification. LCMS: MH⁺=125.

Preparative Example 203

By essentially the same procedure set forth in Preparative Example 202only substituting the compound prepared in Preparative Example 201, thecompound shown above was prepared. LCMS: MH⁺=125.

Preparative Example 204

To 4-N-t-Butoxycarbonylaminopiperidine (0.8 g, 4.0 mmol) in CH₂Cl₂ (10mL) at 0° C. was added TEA (1.40 mL, 2.5 eq.) and 3-trifluoromethylbenzoyl chloride (1.05 g, 1.25 eq.). The resulting solution was stirred15 minutes and warmed to room temperature and stirred 3 hours. Thereaction mixture was diluted with CH₂Cl₂ and washed with 5% Na₂CO₃(2×100 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated to yield a pale yellow solid (quantitative crude yield).

Preparative Example 205

To a solution of the compound prepared in Preparative Example 204 (1.0g, 2.76 mmol) in CH₂Cl₂ (15 mL) at 0° C. was added TFA (8 mL) and theresulting solution was stirred at 0° C. for 30 minutes and roomtemperature 1 hour. The reaction mixture was poured onto Na₂CO₃ (40 g)and H₂O (400 mL) added and the resulting mixture was extracted withCH₂Cl₂. The combined organics were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude product was purified byflash chromatography using a 20% (7N NH₃ in MeOH) solution in CH₂Cl₂ aseluent (0.6 g, 82% yield).

Preparative Examples 206

Step A:

To a solution of 6-chloronicotinamide (1 g, 6.39 mmol) in isoamylalcohol (15 mL) at rt was added Na₂CO₃ (0.81 g, 7.67 mmol) followed bymethoxyethylamine (0.67 mL, 7.67 mmol). The mixture was heat at 130° C.for 16 h, cooled to rt, and was filtered thru a medium glass-frittedfilter. The resulting filtrate was concentrated under reduced pressureand the resultant solid was triturated with Et₂O (2×10 mL). The crudesolid was placed under high vacuum to afford 1.2 g (96%) of a lightyellow solid. M+H=196.

Step B:

To a solution of amide (1.2 g, 6.12 mmol) from Preparative Example 206,Step A in THF (5 mL) at 0° C. was added a solution of BH₃-THF (43 mL; 43mmol) dropwise over 10 min. The resultant solution was warmed to rt andstirred for 14 h. The mixture was cooled to 0° C. and was sequentiallytreated with 6M HCl (35 mL), water (30 mL), and MeOH (150 mL). Themixture was stirred for 8 h and was concentrated under reduced pressure.The crude residue was triturated with MeOH, concentrated under reducedpressure, and placed under high vacuum to afford 1.6 g (82%) of a whitesolid as the dihydrochloride salt. M+H (free base)=182.0. This materialwas used crude in the coupling with 7-Cl adducts.

Preparative Examples 207-211

By essentially the same known procedure set forth in Preparative Example206 only by utilizing the amines shown in Column 2 of Table 13 and theamines shown in Column 3 of Table 13 were prepared: TABLE 13 CMPD Column2 Column 3 M + H (free Prep. Ex. (Amine) (Amine) base) 207

M + H = 138 208

M + H = 152 209

M + H = 178 210

M + H = 195 211

M + H = 207

Preparative Example 212

The above compound was prepared accordingly to the methods described inWO 91/18904.

Preparative Example 213

The above compound was prepared accordingly to the methods described inU.S. Pat. No. 6,180,627 B1.

Preparative Example 214

The known amine was prepared as described in J. Med. Chem. (2001), 44,4505-4508.

Preparative Example 215

The known amine was prepared as described in J. Med. Chem. (1997), 40,3726-3733.

Preparative Example 216

Step A:

A solution of aldehyde (50 g, 0.41 mol) [WO 0232893] in MeOH (300 mL)was cooled to 0° C. and carefully treated with NaBH₄ (20 g, 0.53 mol in6 batches) over 20 minutes. The reaction was then allowed to warm to 20°C. and was stirred for 4 hours. The mixture was again cooled to 0° C.,carefully quenched with saturated aqueous NH₄Cl, and concentrated. Flashchromatography (5-10% 7N NH₃-MeOH/CH₂Cl₂) provided the primary alcohol(31 g, 62%) as a light yellow solid.

Step B:

A slurry of alcohol (31 g, 0.25 mol) from Preparative Example 216, StepA in CH₂Cl₂ (500 mL) was cooled to 0° C. and slowly treated with SOCl₂(55 mL, 0.74 mol over 30 minutes). The reaction was then stirredovernight at 20° C. The material was concentrated, slurried in acetone,and then filtered. The resulting beige solid was dried overnight invacuo (38.4 g, 52%, HCl salt).

Step C:

To a 15 mL pressure tube charged with a stir bar was added chloride (150mg, 0.83 mmol) from Preparative Example 216, Step B followed by 7 MNH₃/MeOH (10 mL). The resulting solution was stirred for 48 h at rtwhere upon the mixture was concentrated under reduced pressure to afforda light yellow solid (0.146 g, 83%). M+H (free base)=140.

Preparative Example 217

The above compound was prepared accordingly to methods described in WO00/26210.

Preparative Example 218

The above compound was prepared accordingly to methods described in WO99/10325.

Preparative Example 219

The known amine dihydrochloride was prepared according to methodsdescribed in WO 02/64211.

Preparative Example 220

The above compound was prepared according to methods described in WO02/64211.

Preparative Example 221

The known primary alcohol was prepared according to WO 00/37473 and wasconverted to the desired amine dihydrochloride in analogous fashion asPreparative Example 220 according to WO 02/064211.

Preparative Example 222

Step A:

To a solution of aldehyde (WO 02/32893) (0.46 g, 2.07 mmol) in MeOH/THF(2 mL/2 mL) at 0° C. was added NaBH₄ (94 mg, 2.48 mmol) in one portion.The resulting mixture was stirred for 12 h at rt and was diluted withsat. aq. NH₄Cl (3 mL). The mixture was concentrated under reducedpressure and the resultant aqueous layer was extracted with CH₂Cl₂ (3×5mL). The organic layers were combined, washed with brine (1×5 mL), dried(Na₂SO₄), and filtered. The organic layer was concentrated under reducedpressure to afford 417 mg (90% yield) of a white solid. M+H=225.

Step B:

The crude alcohol from Preparative Example 222, step A (0.4 g, 1.78mmol) in CH₂Cl₂ (4 mL) was added SOCl₂ (0.65 mL, 8.91 mmol) and themixture was stirred for 2 h at rt. The mixture was concentrated underreduced pressure to afford 407 mg (94%) of a light yellow solid.M+H=243. The crude product was taken on without further purification.

Step C:

To a solution of crude chloride from Preparative Example 222, Step B(0.33 g, 1.36 mmol) in a pressure tube charged with 7M NH₃/MeOH (35 mL)and the mixture was stirred for 72 h. The mixture was concentrated underreduced pressure to afford 257 mg (85%) of a yellow semisolid. M+H (freebase)=224.

Preparative Example 223

To a round bottom flask charged with amine hydrochloride (0.24 g, 1.1mmol) from Preparative Example 222 and a stir bar was added 4NHCl/dioxane (10 mL). The resulting solution was stirred for 12 h at rt,concentrated under reduced pressure, and triturated with CH₂Cl₂ (3×5mL). The crude product was filtered, washed with Et₂O (2×5 mL), anddried under high vacuum to afford 0.19 g (91%) as the dihydrochloridesalt. M+H (free base)=124.

Preparative Example 224

Pd(PPh₃)₄ (0.404 gm, 0.35 mmol) was added to a degassed solution of4-cyanobenzene boronic acid (1.029 g, 7 mmol) and 2-bromopyridine (1.11g, 7 mmol) in 75 mL acetonitrile. 0.4 M sodium carbonate solution (35mL) was added to the reaction mixture and the resulting solution wasrefluxed at 90° C. under Ar for 24 hours (progress of reaction wasmonitored by TLC). The reaction mixture was cooled and aqueous layer wasseparated. The organic layer containing the product and spent catalystwas mixed with silica gel (15 g) and concentrated to dryness. The4-(2-pyridyl)-benzonitrile was isolated by column chromatography (0.850g, 68%). LCMS: MH⁺=181; ¹H NMR (CDCl₃) δ 8.85 (d, 1H), 8.7 (dd, 1H), 7.9(dd, 1H), 7.75 (d, 2H), 7.7 (d, 2H), 7.4 (dd, 1H).

Preparative Examples 225-228

By following essentially same procedure described in Preparative Example224, only substituting the bromides in column 2 of Table 14, compoundsin column 3 of Table 14 were prepared. TABLE 14 Prep. Ex. Column 2Column 3 Column 4 225

Yield = 70% LCMS: MH⁺ = 187 226

Yield = 60% LCMS: MH⁺ = 187 227

Yield = 70% LCMS: MH⁺ = 186 228

Yield = 70% LCMS: MH⁺ = 200

Preparative Example 229

BH₃-THF solution (1 M, 24 mL, 5 eq) was added slowly to a stirringsolution of 4-(2-pyridyl)-benzonitrile (0.85 g, 4.72 mmol) in anhydrousTHF (25 mL) under Ar, and the resulting solution was refluxed for about12 hr. The solution was cooled to 0° C. using ice-water. Methanol (15mL) was added drop-wise to the cold reaction mixture and stirred for 1 hto destroy excess BH₃. Added HCl-methanol (1M, 10 mL) slowly to thereaction mixture and refluxed for 5 h. Concentrated the solution todryness and the residue was dissolved in 25 mL water and extracted withether to remove any un-reacted material. The aqueous solution wasneutralized with solid potassium carbonate to pH 10-11. The free amine,thus formed was extracted with ether, dried over potassium carbonate(0.45 g, 50%). LCMS: MH⁺=185; ¹H NMR (CDCl₃) δ8.85 (d, 1H), 8.7 (dd,1H), 7.9 (dd, 1H), 7.75 (d, 2H), 7.7 (d, 2H), 7.4 (dd, 1H), 3.7 (t, 2H),1.7 (t, 2H).

Preparative Examples 230-233

By following essentially the same procedure set forth in PreparativeExample 229, compounds in column 3 of Table 15 were prepared. TABLE 15Prep. Ex. Column 2 Column 3 Column 4 230

Yield = 60% LCMS: MH⁺ = 191 231

Yield = 60% LCMS: MH⁺ = 191 232

Yield = 70% LCMS: MH⁺ = 190 233

Yield = 70% LCMS: MH⁺ = 204

Preparative Example 234

Step A:

A mixture 4-fluorobenzonitrile (3 g, 25 mmol) and imidazolyl sodium(2.48 g, 27.5 mmol) in DMF (50 mL) was stirred at 80° C. under Ar for 12h. Progress of reaction was monitored by TLC. The reaction mixture wasconcentrated in vacuo and the residue was diluted with 50 mL water andstirred. The aqueous mixture was extracted with EtOAc (2×50 mL).Combined EtOAc extracts was dried over anhydrous MgSO₄, concentrated,and the 4-(1-imidazolyl)-benzonitrile was isolated by columnchromatography (3.6 g, 78%). LCMS: MH⁺=170; ¹H NMR (CDCl₃) δ 8.0 (s,1H), 7.5 (d, 2H), 7.4 (m, 3H), 7.3 (d, 1H)

Step B:

4-(1-imidazolyl)-benzonitrile (1 g, 5.92 mmol) was dissolved inanhydrous THF (10 mL) and added drop-wise to a stirring solution ofLAH-THF (1 M in THF, 18 mL) at room temperature. The reaction mixturewas refluxed under Ar for 2 h and the progress was monitored by TLC. Themixture was cooled to 0° C. and quenched by drop-wise addition of asaturated Na₂SO₄—H₂O solution. The mixture was stirred for 1 h andfiltered to remove lithium salts. The filtrate was dried over anhydrousMgSO₄ and concentrated to obtain 4-(1-imidazolyl)-benzylamine (0.8 g,80%). LCMS: MH⁺=174.

Preparative Example 235

A mixture of 4-(5-oxazolyl)benzoic acid (1.0 g, 5.46 mmol) and Et₃N (552mg, 5.46 mmol) in 25 mL of THF was cooled to 0° C. and ClCOOi-Bu (745mg, 5.46 mmol) was added dropwise. After the addition was over, thereaction mixture was stirred for additional 5 min and then aq NH₄OH(0.63 mL of 28% solution, 10.46 mmol) was added. After overnightstirring, the solvent was evaporated, the residue was taken up in waterand basified to pH 9. The precipitated solid was filtered, washed withwater and dried over P₂O₅ in a vacuum desiccator to provide 500 mg (48%)of the 4-(5-oxazolyl)-benzamide: ¹H NMR (DMSO-d6) δ 8.50 (s, 1H),8.20-7.80 (m, 5H).

Preparative Example 236

A suspension of 4-(5-oxazolyl)benzamide (500 mg, 2.657 mmol) in 10 mL ofdry THF was cooled to 0° C. and 10 mL of 1 M BH₃.THF (10.00 mmol) wasadded. The contents were refluxed overnight and the excess borane wasdestroyed by dropwise addition of methanol. The solvent was evaporatedand the residue was treated with methanolic HCl to decompose theamine-borane complex. After evaporation of the methanol, the residue wastaken in water, basified to pH 10 and the product was extracted in toDCM. The DCM layer was dried (K₂CO₃) and the solvent was removed toprovide 150 mg (32%) of 4-(5-oxazolyl)benzylamine: ¹H NMR (CDCl₃) δ 7.90(s, 1H), 7.60 (d, 2H), 7.40 (d, 2H), 7.30 (s, 1H), 3.90 (s, 2H).

Preparative Examples 237-239

By essentially the same procedures set forth above, the compounds inColumn 2 of Table 16 were reduced using the method indicated in Column 3of Table 16 to give the amine indicated in Column 4 of Table 16. TABLE16 Prep. Ex. Column 2 Column 3 Column 4 CMPD 237

BH₃

¹H NMR (CDCl₃) δ7.15-6.90 (m, 3H), 3.85 (s, 2H), 1.45 (s, 2H) 238

H₂

¹H NMR (CDCl₃) δ8.40 (s, 1H), 7.55 (dd, 1H), 7.10 (d, 1H), 3.85 (s, 2H),2.50 (s, 3H), 1.70 (bs, 2H) 239

BH₃

Preparative Example 240

Prepared by the literature procedure (PCT Int. Appl, WO 0105783): ¹H NMR(CDCl₃) δ7.35 (d, 1H), 7.24-7.10 (m, 2H), 7.02 (d, 1H), 3.95 (t, 1H),3.70 (d, 1H), 3.37 (d, 1H), 2.65 (m, 2H), 2.45 (s, 3H), 1.90 (bs, 2H)

Preparative Example 241 3-(AMINOMETHYL)PIPERIDINE-1-CARBOXAMIDE

A. 3-(tert-BUTOXYCARBONYLAMINOMETHYL)PIPERIDINE-1-CARBOXAMIDE

3(R/S)-(tert-Butoxycarbonylaminomethyl)piperidine (3 g, 14.0 mmoles) wasdissolved in anhydrous dichloromethane (50 mL) andtrimethylsilylisocyanate (9.68 g, 11.4 mL, 84.0 mmoles) was added. Themixture was stirred under argon at 25° C. for 68 h. Additionaltrimethylsilylisocyanate (4.84 g, 5.7 mL, 42.0 mmoles) was added and themixture was stirred at 25° C. for a total of 90 h. The mixture wasevaporated to dryness and chromatographed on a silica gel column (30×5cm) using 2% (10% conc. ammonium hydroxide in methanol)-dichloromethaneas the eluant to give3-(tert-butoxycarbonylaminomethyl)piperidine-1-carboxamide (3.05 g,85%): FABMS: m/z 258.1 (MH⁺); HRFABMS: m/z 258.1816 (MH⁺). Calcd. forC₁₂H₂₄O₃N₃: m/z 258.1818; δ_(H) (CDCl₃) 1.22 91H, m, CH₂), 1.42 (9H, s,—COOC(CH ₃)₃), 1.48 (1H, m, CH₂), 1.67 (2H, m, CH₂), 1.78 (1H, m, CH),2.80 (1H, m, CH₂), 2.99, 3H, m, CH₂), 3.59 (1H, m, CH₂0 3.69 (1H, m,CH₂), 4.76 (2H, bm, CONH₂) and 4.98 ppm (1H, bm, NH); δ_(C) (CDCl₃) CH₃:28.5, 28.5, 28.5; CH₂: 24.0, 28.3, 43.2, 45.1, 47.8; CH: 36.5; C: 79.4,156.3, 158.5.

B. 3-(AMINOMETHYL)PIPERIDINE-1-CARBOXAMIDE

3-(tert-Butoxycarbonylaminomethyl)piperidine-1-carboxamide (150 mg,0.583 mmoles) (prepared as described in Preparative Example 241, Step Aabove) was dissolved in methanol (3 mL). 10% conc. sulfuric acid in1,4-dioxane (7.9 mL) was added and the mixture was stirred at 25° C. for1 h. The mixture was diluted with methanol and BioRad AG1-X8 resin (OH⁻form) was added until the pH was basic. The resin was filtered off,washed with methanol, evaporated to dryness and chromatographed on asilica gel column (15×2 cm) using dichloromethane followed by 15% (10%conc, ammonium hydroxide in methanol)-dichloromethane as the eluant togive the 3-(aminomethyl)piperidine-1-carboxamide (80 mg, 87%): FABMS:m/z 158.1 (MH⁺); HRFABMS: m/z 158.1294 (MH⁺). Calcd. for C₇H₁₆N₃O: m/z158.1293; δ_(H) (CDCl₃+drop CD₃OD) 1.20 (1H, m, CH₂), 1.48 (1H, m, CH₂),1.60 (1H, m, CH), 1.68 (1H, m, CH₂), 1.83 (1H, m, CH₂), 2.64 (bm, 2H,—CH₂NH ₂), 2.82 (1H, m, CH₂), 3.02 (1H, m, CH₂), 2.98 (2H, m, CH₂), 3.70(1H, m, —CH ₂NH₂), 3.78 (1H, m, —CH ₂NH₂) and 5.24 ppm (1H, bs, NH);δ_(C) (CDCl₃+drop CD₃OD) CH₂: 24.1, 28.6, 44.0, 44.8, 47.9; CH: 38.3; C,159.0.

Preparative Example 242 3-(2-AMINOETHYL)PIPERIDINE-1-CARBOXAMIDE

A. 3-(2-tert-BUTOXYCARBONYLAMINOETHYL)PIPERIDINE-1-CARBOXAMIDE

3-(2-tert-Butoxycarbonylaminoethyl)piperidine (500 mg, 2.19 mmoles) wasdissolved in anhydrous dichloromethane (10 mL) andtrimethylsilylisocyanate (2.96 mL, 21.9 mmoles) was added. The mixturewas stirred under argon at 25° C. for 3.35 h. The mixture was dilutedwith dichloromethane and washed with saturated aqueous sodiumbicarbonate. The organic layer was dried (MgSO₄), filtered, evaporatedto dryness and chromatographed on a silica gel column (15×5 cm) using 5%(10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluantto give 3-(2-tert-butoxycarbonylaminoethyl)piperidine-1-carboxamide(417.7 mg, 70%): FABMS: m/z 272.0 (MH⁺); HRFABMS: m/z 272.1979 (MH⁺).Calcd. for C₁₃H₂₆O₃: m/z 272.1974; δ_(H) (CDCl₃) 1.16 (1H, m, CH₂),1-30-1.60 (5H, m, CH/CH₂), 1.46 (9H, s, —COOC(CH ₃)₃), 1.68 (1H, m,CH₂), 1 84 (1H, m, CH₂), 2.54 (1H, dd, CH₂), 2.73 (1H, m, CH₂), 3.08(1H, m, CH₂), 3.42 (1H, m, CH₂), 4.02 (1H, m, CH₂), 4.10 (1H, m, CH₂),4.84 (1H, m, NH) and 4.96 ppm (2H, bm, CONH₂); δ_(C) (CDCl₃) CH₃: 28.5,28.5, 28.5; CH₂: 25.2, 31.7, 34.9, 37.3, 44.6, 50.3; CH: 32.9; C: 79.5,156.4, 158.2.

B. 3-(2-AMINOETHYL)PIPERIDINE-1-CARBOXAMIDE

3-(2-tert-Butoxycarbonylaminoethyl)piperidine-1-carboxamide (392.7 mg,1.45 mmoles) (prepared as described in Preparative Example 242, Step Aabove) was dissolved in methanol (7.5 mL) and 10% conc. sulfuric acid in1,4-dioxane (19.5 mL) was added. The mixture was stirred at 25° C. for1.25 h. The mixture was diluted with methanol and BioRad AG1-X8 resin(OH⁻ form) was added until the pH was basic. The resin was filtered off,washed with methanol, evaporated to dryness and chromatographed on asilica gel column (30×2.5 cm) using 15% (10% conc, ammonium hydroxide inmethanol)-dichloromethane as the eluant to give3-(2-aminoethyl)piperidine-1-carboxamide (233 mg, 94%): FABMS: m/z 172.1(MH⁺); HRFABMS: m/z 172.1444 (MH⁺). Calcd for C₈H₁₈N₃O requires: m/z172.1450; δ_(H) (CDCl₃+3% CD₃OD) 1.14 (1H, m, CH₂), 1.40 (2H, m, CH₂),1.49 (1H, m, CH), 1.58 (1H, m, CH₂), 1.69 (1H, m, CH₂), 1.85 (1H, m,CH₂), 2.55 (1H, m, CH₂), 2.67 (5H, m, CH₂/NH₂), 2.76 (1H, bm, CH₂), 2.84(1H, m, CH₂) and 3.82 ppm (2H, m, CONH₂); δ_(C) (CDCl₃+3% CD₃OD) CH₂:24.8, 30.9, 36.6, 38.9, 44.9, 50.0; CH: 33.4.

Preparative Example 243 4-(2-AMINOETHYL)PIPERIDINE-1-CARBOXAMIDE

A. 4-(2-tert-BUTOXYCARBONYLAMINOETHYL)PIPERIDINE-1-CARBOXAMIDE

4-(2-tert-Butoxycarbonylaminoethyl)piperidine (500 mg, 2.19 mmoles) wasdissolved in anhydrous dichloromethane (10 mL) andtrimethylsilylisocyanate (2.96 mL, 21.9 mmoles) was added. The mixturewas stirred under argon at 25° C. for 3.25 h. The mixture was dilutedwith dichloromethane and washed with saturated aqueous sodiumbicarbonate. The organic layer was dried (MgSO₄), filtered, evaporatedto dryness and chromatographed on a silica gel column (15×5 cm) using 5%(10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluantto give 4-(2-tert-butoxycarbonylaminoethyl)piperidine-1-carboxamide(308.2 mg, 52%): FABMS: m/z 272.0 (MH⁺); HRFABMS: m/z 272.1965 (MH⁺).Calcd. for C₁₃H₂₆O₃N₃: m/z 272.1974; δ_(H) (CDCl₃) 1.20 (2H, m, CH₂),1.47 (9H, s, —COOC(CH ₃)₃), 1.45-1.55 (3H, m, CH/CH₂), 1.75 (2H, m,CH₂), 2.82 (2H, m, CH₂), 3.19 (2H, m, CH₂), 3.96 (2H, m, CH₂), 4.64 (2H,m, CH₂) and 4.70 ppm (1H, bm, NH); δ_(C) (CDCl₃) CH₃: 28.5, 28.5, 28.5;CH₂: 31.8, 31.8, 36.7, 38.0, 44.5, 44.5; CH: 33.4; C: 79.2, 156.7,158.1.

A. 3-(2-AMINOETHYL)PIPERIDINE-1-CARBOXAMIDE

4-(2-tert-Butoxycarbonylaminoethyl)piperidine-1-carboxamide (283.3 mg,1.04 mmoles) (prepared as described in Preparative Example 243, Step Aabove) was dissolved in methanol (5.4 mL) and 10% conc. sulfuric acid in1,4-dioxane (14.2 mL) was added and the mixture was stirred at 25° C.for 1.25 h. The mixture was diluted with methanol and BioRad AG1-X8resin (OH⁻ form) was added until the pH was basic. The resin wasfiltered off, washed with methanol, evaporated to dryness andchromatographed on a silica gel column (30×2.5 cm) using 15% (10% conc,ammonium hydroxide in methanol)-dichloromethane as the eluant to givethe 3-(2-aminoethyl)piperidine-1-carboxamide (170 mg, 95%): FABMS: m/z172.1 (MH⁺); HRFABMS: m/z 172.1442. Calcd for C₈H₁₈N₃O requires: m/z172.1450; δ_(H) (CDCl₃+3% CD₃OD) 1.16 (2H, m, CH₂), 1.43 (2H, m, CH₂),1.52 (1H, m, CH), 1.70 (2H, m, CH₂), 2.70-2.85 (8H, m, CH₂) and 3.92 ppm(2H, m, CONH₂); δ_(C) (CDCl₃+3% CD₃OD) CH₂: 31.9, 31.9, 39.0, 39.7,44.4, 44.4; CH: 33.5; C, 158.7.

Preparative Example 244 3-(AMINOMETHYL)-1-METHYLPIPERIDINE

A. 3-(BROMOMETHYL)-1-METHYLPIPERIDINE

3-(Hydroxymethyl)-1-methylpiperidine (2 g, 15.5 mmoles) was dissolved inanhydrous acetonitrile (32 mL) and anhydrous pyridine (2.02 mL, 24.8mmoles) was added and the solution was cooled to 0° C.Dibromotriphenylphosphorane (8.49 g, 20.2 mmoles) was added at 0° C. andthe mixture was allowed to warm up to 25° C. and was stirred for 94 h.The mixture was evaporated to dryness and the residue waschromatographed on a silica gel column (30×5 cm) using gradient elutionwith dichloromethane, 35% diethyl ether in dichloromethane and 5-10%methanol in dichloromethane as the eluant to give3-(bromomethyl)-1-methylpiperidine (3.13 g, 100%): FABMS: m/z 192.1(MH⁺); δ_(H) (CDCl₃) 1.52 (1H, m, CH₂), 1.99 (2H, m, CH₂), 2.43 (1H, m,CH₂), 2.75 (2H, m, CH₂), 2.82 (1H, m, CH), 2.86/2.88 (3H, s, NCH₃),3.42/3.49 (2H, dd, —CH ₂Br) and 3.56 ppm (2H, m, CH₂); δ_(C) (CDCl₃)CH₃: 44.3; CH₂: 22.1, 26.6, 35.4, 54.8, 58.2; CH: 34.6.

A. 3-(Di-tert-BUTOXYCARBONYLAMINOMETHYL)-1-METHYLPIPERIDINE

3-(Bromomethyl)-1-methylpiperidine (1.5 g, 7.81 mmoles) (fromPreparative Example 244, Step A above) anddi-tert-butyliminodicarboxylate (1.697 g, 7.81 mmoles) were dissolved inanhydrous acetonitrile (25 mL). Cesium carbonate (5.1 g, 15.6 mmoles)and lithium iodide (52 mg, 0.391 mmoles) were added and the mixture wasstirred at 70° C. for 20 h. The mixture was evaporated to dryness andthe residue was partitioned between dichloromethane and saturatedaqueous sodium bicarbonate. The organic layer was dried (MgSO₄),filtered and evaporated to dryness. the residue was chromatographed on asilica gel column (30×5 cm) using 3% methanol in dichloromethane as theeluant to give 3-(di-tert-butoxycarbonylamino)-1-methylpiperidine (1.331g, 52%): FABMS: m/z 329.2 (MH⁺); HRFABMS: m/z 329.2438 (MH⁺). Calcd. forC₁₇H₃₃N₂O₄: m/z 329.2440; δ_(H) (CDCl₃) 1.10 (1H, m, CH₂), 1.54 (18H, s,—COOC(CH₃)₃), 1.86 (2H, m, CH₂), 2.01 (1H, m, CH₂), 2.19 (1H m, CH),2.34 (2H, bm, CH₂), 2.59 (3H, —NCH₃), 3.19 (2H, m, CH₂) and 3.52/3.52ppm (2H, —CH₂N—); δ_(C) (CDCl₃) CH₃: 28.5, 28.5, 28.5, 28.5, 28.5, 28.5,47.2; CH₂: 25.4, 28.3, 50.4, 56.8, 60.8; CH: 37.2; C: 83.0, 83.0, 153.5,153.5.

A. 3-(AMINOMETHYL)-1-METHYLPIPERIDINE

3-(Di-tert-butoxycarbonylamino)-1-methylpiperidine (500 mg, 1.52 mmoles)(from Preparative Example 244, Step B above) was dissolved in methanol(7.5 mL) and 10% (v/v) conc. sulfuric acid in 1,4-dioxane (19.75 mL) wasadded. The solution was stirred at 25° C. for 0.5 h. Methanol (300 mL)was added, followed by BioRad AG1-X8 resin (OH⁻ form) until the pH was˜10. The resin was filtered off and washed with methanol (2×200 mL). Thecombined eluates were evaporated to dryness and the residue waschromatographed on a silica gel column (30×2.5 cm) using 10% (10% conc.ammonium hydroxide in methanol)-dichloromethane as the eluant to give3-(aminomethyl)-1-methylpiperidine (69.2 mg, 35%): FABMS: m/z 129.1(MH⁺); HRFABMS: m/z 129.1392 (MH⁺). Calcd. for C₇H₁₇N₂: m/z 129.1392;δ_(H) (CDCl₃) 0.90 (2H, m, CH₂), 1.65 (2H, m, CH₂), 1.72 (1H, m, CH),1.79 (1H, m, CH₂), 1.91 (1H, m, CH₂), 2.30 (3H, s, —NCH₃), 2.64 (2H, m,CH₂), 2.82 (1H, m, —CH ₂NH₂) and 2.92 ppm (1H, m, —CH ₂NH₂); δ_(C)(CDCl₃) CH₃: 46.7; CH₂: 25.2, 28.0, 46.3, 56.4, 60.3; CH: 39.9.

Preparative Example 245 4-(AMINOMETHYL)-1-METHYLPIPERIDINE

A. 1-METHYLISONIPECOTAMIDE

Isonipecotamide (10 g, 78.0 mmoles) was dissolved in distilled water(100 mL) and 37% aqueous formaldehyde (7.6 mL, equivalent to 2.81 gHCHO, 93.6 mmoles) was added. Wet 10% Pd—C (8 spoon spatulas) was addedunder argon and the mixture was hydrogenated at 25° C. and 50 psi for 43h. The catalyst was filtered off through Celite and the latter washedwith water and methanol. The combined filtrates were evaporated todryness and the residue was chromatographed on a silica gel column (60×5cm) using 8%-10%-20% (10% conc. ammonium hydroxide inmethanol)-dichloromethane as the eluant to give 1-methylisonipecotamide(7.15 g, 64%): FABMS: m/z 143.1 (MH⁺); HRFABMS: m/z 143.1184 (MH⁺).Calcd. for C₇H₁₅N₂O: m/z 143.1184; δ_(H) (d₆-DMSO) 1.50/1.57 (4H, m,CH₂), 1.76/1.94 (4H, m, CH₂), 2.10 (3H, s, —NCH₃), 2.72 (1H, m, CH) and6.68/7.18 ppm (2H, m, CONH₂); δ_(C) (d₆-DMSO)CH₃: 41.2; CH₂: 28.5, 28.5,54.9, 54.9; CH: 46.2; C, 176.7.

B. 4-(AMINOMETHYL)-1-METHYLPIPERIDINE

1-Methylisonipecotamide (6.75 g, 47.5 mmoles) (prepared as described inPreparative Example 245, Step A above) was dissolved in anhydrous THF(350 mL) and the resulting mixture was added in portions to a stirredslurry of lithium aluminum hydride (1.8 g, 47.5 mmoles) in anhydrous THF(100 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for30 min and then heated at 66° C. for 25 h under nitrogen. Distilledwater (1.88 mL) was added dropwise to the stirred mixture at 0° C.,followed by 20% aqueous sodium hydroxide (1.42 mL) and then distilledwater (6.75 mL) and the mixture was stirred for 15 min. The mixture wasfiltered and the solids were washed with THF and dichloromethane. Thecombined filtrates were evaporated to dryness and chromatographed on asilica gel column (30×5 cm) using 15%-20% (10% conc. ammonium hydroxidein methanol)-dichloromethane as the eluant to give4-(aminomethyl)-1-methylpiperidine (0.678 g, 11%): FABMS: m/z 129.1(MH⁺); HRFABMS: m/z 129.1389 (MH⁺). Calcd. for C₇H₁₇N₂: m/z 129.1392;δ_(H) (d₆-DMSO): 2.08 ppm (3H, s, —NCH₃); δ_(C) (d₆-DMSO): CH₃: underDMSO peaks; CH₂: 29.6, 29.6, 46.7, 55.2, 55.2; CH: 46.2.

Preparative Example 246 3-(AMINOMETHYL)BENZONITRILE

A. 3-(Di-tert-BUTOXYCARBONYLAMINO)BENZONITRILE

3-(Bromomethyl)benzonitrile (5 g, 25.5 mmoles) anddi-tert-butyliminodicarboxylate (5.54 g, 25.5 mmoles) were dissolved inanhydrous THF (50 mL) and cesium carbonate (16.62 g, 25.5 mmoles) andlithium iodide (170.5 mg, 1.275 mmoles) were added. The mixture wasstirred at 70° C. for 22 h and the reaction was worked up as describedin Preparative Example 89, Step B above. The residue was chromatographedon a silica gel column (60×5 cm) using 5% ethyl acetate in hexane as theeluant to give 3-(di-tert-butoxycarbonylamino)benzonitrile (7.39 g,87%): FABMS: m/z 333.2 (MH⁺); HRFABMS: m/z 333.1815 (MH⁺); Calcd. forC₁₈H₂₅N₂O₄: m/z 333.1814; δ_(H) (CDCl₃) 1.52 (18H, s, —COOC(CH₃)₃), 4.84(2H, s, CH₂), 7.48 (1H, m, Ar—H), 7.60 (2H, m, Ar—H) and 7.65 ppm (1H,m, Ar—H); δ_(C) (CDCl₃) CH₃: 28.1, 28.1, 28.1, 28.1, 28.1, 28.1; CH₂:48.4; CH: 129.2, 131.0, 131.0, 131.9; C: 83.2, 83.2, 112.5, 118.8,140.1, 152.5, 152.5.

B. 3-(AMINOMETHYL)BENZONITRILE

3-(Di-tert-butoxycarbonylamino)benzonitrile (2 g, 6.0 mmoles) (preparedas described in Preparative Example 246, Step A above) was dissolved inmethanol (30 mL) and 10% (v/v) (10% conc. sulfuric acid in 1,4-dioxane)(79 mL) was added. The solution was stirred at 25° C. for 0.25 h andworked up as described in Preparative Example 89, Step C above). Theresidue was chromatographed on a silica gel column (15×5 cm) using 3%(10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluantto give the title compound (651.4 mg, 82%): FABMS: m/z 133.1 (MH⁺);HRFABMS: m/z 133.0762 (MH⁺). Calcd. for C₈H₉N₂: m/z 133.0766; δ_(H)(CDCl₃) 2.57 (2H, s, —CH₂NH ₂), 3.92 (2H, s, —CH ₂NH₂), 7.46 (1H, m,Ar—H), 7.57 (2H, m, Ar—H) and 7.64 ppm (1H, m, Ar—H); δ_(C) (CDCl₃) CH₂:45.2; CH: 129.4, 130.7, 130.7, 131.8; C: 112.4, 118.8, 143.8.

Preparative Example 247 4-(AMINOMETHYL)BENZONITRILE

A. 3-(Di-tert-BUTOXYCARBONYLAMINOMETHYL)BENZONITRILE

4-(Bromomethyl)benzonitrile (5 g, 25.5 mmoles) anddi-tert-butyliminodicarboxylate (5.54 g, 25.5 mmoles) were dissolved inanhydrous THF (50 mL) and cesium carbonate (16.62 g, 25.5 mmoles) andlithium iodide (170.5 mg, 1.275 mmoles) were added. The mixture wasstirred at 70° C. for 23 h and the reaction was worked up as describedin Preparative Example 244, Step B above. The residue waschromatographed on a silica gel column (50×5 cm) using 5% ethyl acetatein hexane as the eluant to give4-(di-tert-butoxycarbonylaminomethyl)benzonitrile (7.07 g, 83%): FABMS:m/z 333.2 (MH⁺); HRFABMS: m/z 333.1816 (MH⁺). Calcd. for C₁₈H₂₅N₂O₄: m/z333.1814; δ_(H) (CDCl₃) 1.45 (18H, s, —COOC(CH₃)₃), 4.81 (2H, s, CH₂),7.37 (2H, d, Ar—H) and 7.62 ppm (2H, d, Ar—H); δ_(C) (CDCl₃) CH₃: 28.1,28.1, 28.1, 28.1, 28.1, 28.1; CH₂: 49.2; CH: 127.8, 127.8, 132.3, 132.3;C: 83.2, 83.2, 111.1, 118.9, 144.1, 152.4, 152.4.

B. 4-(AMINOMETHYL)BENZONITRILE

4-(Di-tert-butoxycarbonylaminomethyl)benzonitrile (2 g, 6.0 mmoles)(prepared as described in Preparative Example 247, Step A above) wasdissolved in TFA (4 mL) and the solution was stirred at 25° C. for 0.25h. The reaction mixture was diluted with dichloromethane and extractedwith 1N sodium hydroxide. The organic layer was dried (MgSO₄), filteredand evaporated to dryness. The residue was chromatographed on a silicagel column (15×5 cm) using 3% (10% conc. ammonium hydroxide inmethanol)-dichloromethane as the eluant to give4-(aminomethyl)benzonitrile (108 mg, 68%): FABMS: m/z 133.1 (MH⁺);HRFABMS: m/z 133.0764 (MH⁺). Calcd. for C₈H₉N₂: m/z 133.0766; δ_(H)(CDCl₃) 2.04 (2H, s, —CH₂NH ₂), 3.89 (2H, s, —CH ₂NH₂), 7.40 (2H, d,Ar—H) and 7.59 ppm (2H, d, Ar—H); δ_(C) (CDCl₃)CH₂: 45.7; CH: 127.8,127.8, 132.4, 132.4; C: 110.6, 118.9, 148.0.

Preparative Example 248

To a solution of (1S,2S)-2-benzyloxycyclopentyl amine (1.5 g, 7.84 mmol)in MeOH (50 mL) at rt was added 10% Pd/C (50% wet, 1.0 g) followed bydropwise addition of conc. HCl (0.7 mL). The mixture was stirred under aballoon of H₂ for 14 h and the catalyst was filtered off thru a pad ofCelite. The pad of Celite washed with MeOH (2×10 mL) and the resultingfiltrate was concentrated under reduced pressure to afford 0.97 g (90%)of a yellow semisolid; M+H (free base)=102

Preparative Examples 249-251

In an analogous fashion to Preparative Example 248, the benzyl protectedcycloalkyl amines (Column 2) were converted to the desiredaminocycloalkanol hydrochloride derivatives (Column 3) as listed inTable 17. TABLE 17 Column 2 Column 3 CMPD Ex. (Amine) (Cleavage method)M + H 249

M + H = 102 (free base) 250

M + H = 116 (free base) 251

M + H = 116 (free base)

Preparative Example 252

To a solution of ester (prepared according to J. Org. Chem. (1999), 64,330) (0.5 g, 2.43 mmol) in THF (8 mL) at 0° C. was added LiAlH₄ (0.37 g,9.74 mmol) in one portion. The resulting mixture was heated at refluxfor 12 h and was cooled to 0° C. The mixture was treated sequentiallywith H₂O (1 mL), 1 M NaOH (1 mL), and H₂O (3 mL). CH₂Cl₂ (10 ml) wasadded to the mixture which was stirred vigorously for 30 min. Themixture was filtered thru a pad of Celite which washed generously withCH₂Cl₂ (3×5 mL). The resulting filtrate was concentrated under reducedpressure to afford 0.41 g (85%) of a yellow/orange solid. M+H=142.

Preparative Example 253

Step A:

To a solution of L-proline methyl ester hydrochloride (0.50 g, 3.0 mmol)in CH₂Cl₂ (15 mL) at 0° C. was added Et₃N (1.1 mL, 7.55 mmol) followedby TFAA (0.56 mL, 3.92 mmol). The mixture was stirred for 12 h at rt and1N HCl (25 mL) was added. The layers were separated and the organiclayer washed sequentially with sat. aq. NaHCO₃ (1×25 mL), and brine(1×25 mL). The organic layer was dried (Na₂SO₄), filtered, andconcentrated under reduced pressure to afford 0.72 g (100%) of a yellowoil. M+H=226. The crude material was taken onto Step B without furtherpurification.

Step B:

To a solution of the compound prepared in Preparative Example 253, StepA (0.68 g, 3.0 mmol) in THF (20 mL) at 0° C. was added MeMgI (5.1 mL,3.0M in Et₂O) dropwise over 10 min. The resulting solution was stirredfor 16 h at rt whereupon the mixture was quenched by addition of sat.aq. NH₄Cl. The mixture was concentrated to dryness and the resultantresidue was stirred with EtOAc (100 mL) for 45 min and filtered. Thefiltrate was concentrated under reduced pressure to afford 0.68 g (100%)of a yellow/orange oil. M+H=226. The crude material was taken onto StepC without further purification.

Step C:

To a solution of the compound prepared in Preparative Example 253, StepB (0.68 g, 3.0 mmol) in MeOH (5 mL) was added a solution of KOH (0.68 g,12.1 mmol) in MeOH (5 mL). The mixture was stirred at reflux for 12 hand rt for 72 h whereupon the mixture was concentrated to dryness. Thecrude residue was suspended in EtOAc (50 mL) and was stirred vigorouslyfor 30 min and was filtered. This procedure was repeated 2× more and theresultant filtrate was concentrated under reduced pressure to afford 128mg (33%) of a maroon/orange oil. M+H=130. This material was used withoutpurification in the subsequent coupling step.

Preparative Example 254

The aldehyde was prepared according to the procedure of Gupton (J.Heterocyclic Chem. (1991), 28, 1281).

Preparative Example 255

Using the aldehyde from Preparative Example 254, the procedure of Gupton(J. Heterocyclic Chem. (1991), 28, 1281) was employed to prepare thetitle aldehyde.

Preparative Example 256

The title aldehyde was prepared according to the procedure of Ragan et.al Synlett (2000), 8, 1172-1174.

Preparative Example 257

The reaction of known cyclopentyl guanidine hydrochloride (Org. Lett.(2003), 5, 1369-1372) under the conditions of Ragan (Synlett (2000), 8,1172-1174) afforded the title aldehyde.

Preparative Example 258

The title compound was prepared according to known literatureMonatshefte fur Chemie (1973), 104, 1372-1382.

EXAMPLES Example 1

A solution of the product from Preparative Example 127 (0.27 g, 0.875mmol), 4-aminomethylpyridine (0.12 g, 1.3 eq.), and K₂CO₃ (0.24 g, 2eq.) in CH₃CN (5 mL) was stirred at room temperature 48 hours. Thereaction mixture was diluted with H₂O and extracted with CH₂Cl₂. Thecombined organics were dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by flash chromatography using a 4% MeOH inCH₂Cl₂ solution as eluent (0.28 g, 93% yield). LCMS: MH⁺=380; mp=>205°C. (dec).

Examples 2-210

By following essentially the same procedure set forth in Example 1 onlysubstituting the chlorides shown in Column 2 of Table 18 and the aminesshown in Column 3 of Table 18, the compounds in Column 4 of Table 18were prepared: TABLE 18 Ex. Column 2 Column 3 Column 4 Data 2

LCMS: MH⁺ =380; mp =175-176° C. 3

LCMS: MH⁺ =398; mp =156-157° C. 4

LCMS: MH⁺ =398; mp =45-49° C. 5

LCMS: MH⁺ =354; mp =43-46° C. 6

LCMS: MH⁺ =354; mp =149-150° C. 7

LCMS: MH⁺ =414; mp =86-92° C. 8

LCMS: MH⁺ =414; mp =185-186° C. 9

LCMS: MH⁺ =448; mp =167-168° C. 10

LCMS: MH⁺ =346; mp =57-58° C. 11

LCMS: MH⁺ =347; mp =122.9-125.3° C. 12

LCMS: MH⁺ =360; mp =127-128° C. 13

LCMS: MH⁺ =342; mp =133-135° C. 14

LCMS: MH⁺ =344; mp =152-155° C. 15

LCMS: MH⁺ =362; mp =164-167° C. 16

LCMS: MH⁺ =327; mp =146-155° C. 17

LCMS: MH⁺ =332; mp =71-82° C. 17.1

MS: MH⁺ =332. 18

LCMS: MH⁺ =346; mp =58-65° C. 19

LCMS: MH⁺ =414; mp =211-213° C. 20

LCMS: MH⁺ =414; mp =194-197° C. 21

MS: MH⁺ =414 m.p. 211-216° C. 22

LCMS: MH⁺ =544; mp =104-107° C. 23

Yield =83% LCMS: MH⁺ =410. 24

Yield =84% LCMS: MH⁺ =410. 25

Yield =96% LCMS: MH⁺ =440. 26

Yield =99% LCMS: MH⁺ =440. 27

Yield =89% LCMS: MH⁺ =448. 28

Yield =78% LCMS: MH⁺ =448. 30

Yield =96% LCMS: MH⁺ =483. 31

Yield =35% LCMS: MH⁺ =483. 32

Yield =77% LCMS: MH⁺ =515. 33

Yield =100% m.p. 179° C. LCMS: MH⁺ =388 34

Yield =99% m.p. 186° C. LCMS: MH⁺ =456 35

Yield =98% m.p. 181° C. LCMS: MH⁺ =401 36

Yield =63% m.p. 192° C. LCMS: MH⁺ =480 37

Yield =75% m.p. 126-127° C. LCMS: MH⁺ =400 38

Yield =94% m.p. 132-133° C. LCMS: MH⁺ =400 39

Yield =95% m.p. 121-122° C. LCMS: MH⁺ =400 40

Yield =98% LCMS: MH⁺ =460 41

Yield =87% m.p. 170-171° C. LCMS: MH⁺ =464 42

Yield =84% m.p. 216-217° C. LCMS: MH⁺ =464 43

Yield =96% m.p. 214° C. LCMS: MH⁺ =464 44

Yield =95% m.p. 158° C. LCMS: MH⁺ =522 45

Yield =90% LCMS: MH⁺ =278 46

Yield =100%; LCMS: MH⁺ = 394 47

LCMS: MH+ =473 m.p. 84-87° C. 48

MS: MH⁺ =396 m.p. 91.5-93.3° C. 49

MS: MH⁺ =396 m.p. 196-199° C. 50

MS: MH⁺ =430 m.p. 242-244° C. 51

MS: MH⁺ =430 m.p. 218° C. 52

MS: MH⁺ =430 m.p. 230-233° C. 54

MS: MH⁺ =405 m.p. 185-188° C. 55

MS: MH⁺ =370 m.p. 229-232° C. 56

MS: MH⁺ =370 m.p. 85-90° C. 57

MS: MH⁺ =386 m.p. 227-230° C. 58

MS: MH⁺ =372 m.p. 212-215° C. 59

MS: MH⁺ =318 m.p. 169-171° C. 60

MS: MH⁺ =332 m.p. 170-173° C. 61

MS: MH⁺ =346 m.p. 156-159° C. 62

MS: MH⁺ =360 m.p. 114-116° C. 63

MS: MH⁺ =348 m.p. 197-200° C. 64

1. mp =230-232 2. M + H =396 65

1. mp =205-207 2. M + H =402 66

1. mp =220-223 2. M + H =414 67

1. mp =191-193 2. M + H =431 68

1. mp =235-237 2. M + H =397 69

1. mp =>250 2. M + H =403 70

1. mp =230-232 2. M + H =415 71

1. mp =235-238 2. M + H =431 72

1. mp =186-188 2. M + H =410 73

1. mp =136-138 2. M + H =424 74

1. mp =192-195 2. M + H =450 75

1. mp =88-90 2. M + H =454 76

1. mp =230-232 2. M + H =467 77

1. mp =131-133 2. M + H =479 78

1. mp =85-88 2. M + H =376 79

1. mp =131-133 2. M + H =388 80

1. mp =206-208 2. M + H =408 81

1. mp =108-110 2. M + H =502 82

1. mp =83-85 2. M + H =402 83

1. mp =220 2. M + H =414 84

1. mp =154-156 2. M + H =426 85

1. mp =152-153 2. M + H =438 86

1. mp =159-161 2. M + H =420 87

1. mp =>220 2. M + H =455 88

1. mp =223-225 2. M + H =425 89

1. mp =199-201 2. M + H =419 90

1. mp =184-186 2. M + H =426 91

1. mp =196-198 2. M + H =420 92

1. mp =156-159 2. M + H =440 93

1. mp =173-176 2. M + H =434 94

1. mp =173-175 2. M + H =452 95

1. mp =174-176 2. M + H =469 96

1. mp =230-234 2. M + H =434 97

1. mp =191-193 2. M + H =441 98

1. mp =202-205 2. M + H =434 99

1. mp =209-212 2. M + H =453 100

1. mp =219-221 2. M + H =469 101

1. mp =64-66 2. M + H =403 102

1. mp =168-170 2. M + H =420 103

1. mp =213-216 2. M + H =411 104

1. mp =98-100 2. M + H =561 105

1. mp 70-72 2. M + H =608 106

1. mp 168-170 2. M + H =538 107

1. mp 189-191 2. M + H =592 108

LCMS: MH⁺ =458; 109

Yield =89 LCMS: MH⁺ =418 m.p. =131-132° C. 110

Yield = 95% LCMS: MH⁺ = 347 111

Yield = 91% 3H); LCMS: MH⁺ = 484 112

Yield = 87% LCMS: MH⁺ = 427 113

Yield = 80% LCMS: MH⁺ = 427 114

Yield = 91% LCMS: MH⁺ = 378 115

Yield = 92%, 3H); LCMS: MH⁺ = 520 116

Yield = 98% LCMS: MH⁺ = 536 117

Yield = 82% LCMS: MH⁺ = 410 118

Yield = 95% LCMS: MH⁺ = 347 121

Yield =65% LCMS: MH⁺ =481.02 126

Yield = 71% MH⁺ = 486 127

Yield = 71% MH⁺ =495.1 128

Yield = 55% MH⁺ = 463 129

Yield =77% LCMS: MH⁺ =455 130

¹H NMR (Yield =75% LCMS: MH⁺ = 379 131

Yield =75% LCMS: MH⁺ = 407 132

Yield =75% LCMS: MH⁺ = 421 133

Yield =70% LCMS: MH⁺ = 421 134

Yield =78% LCMS: MH⁺ =475 135

Yield =75% LCMS: MH⁺ =476 136

Yield =65% LCMS: MH⁺ =455 137

Yield =55% LCMS: MH⁺ =473) 138

Yield =60% LCMS: MH⁺ =439 139

Yield =65% LCMS: MH⁺ =441 140

Yield =80% LCMS: MH⁺ =432 141

Yield =60% LCMS: MH⁺ =429 142

LCMS: MH⁺ = 330; mp =109-111° C. 143

LCMS: MH⁺ = 346; mp =186-188° C. 144

LCMS: MH⁺ = 384; mp =148-150° C. 145

LCMS: MH⁺ = 400; mp =186-188° C. 146

LCMS: M2H⁺ = 390; mp =192-194° C. 147

LCMS: M⁺ = 404; mp =220-222° C. 148

LCMS: MH⁺ = 369; mp >230° C. 149

LCMS: MH⁺ = 364; mp =186-188° C. 150

LCMS: MH⁺ = 312; mp =138-140° C. 151

LCMS: M⁺ = 380; mp =172-174° C. 152

LCMS: MH⁺ = 352; mp =201-203° C. 153

LCMS: MH⁺ = 348; mp =166-168° C. 154

LCMS: M2H⁺ = 531; mp =78-80° C. 155

LCMS: M2H⁺ = 474; mp =161-163° C. 156

LCMS: M⁺ = 444; mp =48-51° C. 157

MH⁺ =542.1 158

MH⁺ =520.1 159

MH⁺ =542.1 160

MH⁺ =480.1 161

MH⁺ =506.1 162

MH⁺ =480.1 163

MH⁺ =494.1 164

MH⁺ =466.1 165

MH⁺ =494.1 166

MH⁺ =508.1 167

MH⁺ =520.1 168

MH⁺ =528.1 169

MH⁺ =520.1 170

MH⁺ =528.1 171

LCMS: MH⁺ =474; 172

LCMS: MH⁺ =437; 173

LCMS: MH⁺ =472; 174

LCMS: MH⁺ =428.1 175

LCMS: MH⁺ =426.2 176

LCMS: MH⁺ =442.0 177

LCMS: MH⁺ =452.0 178

Yield =90 MH⁺ =436 m.pt. =89.1° C. 179

MH⁺ =424 m.pt. =188.2° C. 180

MH⁺ =448 m.pt. =211.3° C. 181

Yield =quant. MH⁺ =464 182

MH⁺ =382 m.pt. =185.8° C. 183

MH⁺ =387 m.pt. =181-182° C. 184

MH⁺ =453 185

MH⁺ =401 m.pt. =178.3° C. 186

MH⁺ =402 187

Yield =91 MH⁺ =386 m.pt. =148.3° C. 188

Yield =64 MH⁺ =402 m.pt. =174.5° C. 189

MH⁺ =379 m.pt. =82-83° C. 190

MH⁺ =379 m.pt. =50.7° C. 191

Yield =89 MH⁺ =469 m.pt. =186.7° C. 192

Yield =93 MH⁺ =410 m.pt. =86.7° C. 193

Yield =76 MH⁺ =333 m.pt. =120.3° C. 194

Yield =86 MH⁺ =353 m.pt. =188.9° C. 195

Yield = 11% LCMS: 374 MH⁺ = 390 196

Yield = 88% LCMS: 374 MH⁺ = 346 197

Yield = 88% LCMS: 374 MH⁺ = 346 198

Yield =MH⁺ =400 m.pt. =111.5-112.2° C. 199

MH⁺ =416 200

MH⁺ =415 201

MH⁺ =398 m.p. =156.5° C. 202

MH⁺ =414 m.p. =89.5° C. 203

MH⁺ =413 204

Yield =86 MH⁺ =521 m.p. =79.9° C. 204.10

204.11

Yield =87 MH⁺ =521 m.p. =128.6° C. 205

Yield =99 MH⁺ =537 m.p. =83.5° C. 206

Yield =94 MH⁺ =598 m.p. =110.8° C. 207

Yield =quant. MH⁺ =545 208

Yield =96 MH⁺ =468 m.p. =69.2° C. 209

MH⁺ =498 m.p. =226.5° C. 210

MH⁺ =564 m.p. =174.2° C.Additional data for select examples given below.

Example 23

¹H NMR (CD₃OD) δ8.63 (d, J=5.7 Hz, 2H), 8.18 (s, 1H), 7.81 (dd, J=8.1Hz, 2.1 Hz, 1H), 7.58 (d, J=6.0 Hz, 2H), 7.48 (m, 1H), 7.15-7.10 (m,2H), 6.50 (s, 1H), 4.86 (s, 2H), 3.70 (s, 3H)

Example 24

¹H NMR (CDCl₃) δ 8.82 (s, 1H), 8.73 (d, J=4.2 Hz, 1H), 8.11 (s, 1H),8.06 (dd, J=7.8 Hz, 1.8 Hz, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.53-7.47 (m,2H), 7.20 (m, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.75 (s, 1H), 4.81 (d, J=4.5Hz, 2H), 3.86 (s, 3H)

Example 25

¹H NMR (CDCl₃) δ8.75 (d, J=5.7 Hz, 2H), 8.12 (s, 1H), 7.81 (d, J=2.1 Hz,1H), 7.53 (dd, J=8.4, 2.1 Hz, 1H), 7.45 (d, J=6.0 Hz, 2H), 6.96 (t,J=6.0 Hz, 2H), 6.33 (s, 1H), 4.85 (d, J=6.0 Hz, 2H), 4.09 (s, 3H), 4.03(s, 3H)

Example 26

¹H NMR (CDCl₃) δ8.82 (s, 1H), 8.72 (s, 1H), 8.09 (m, 1H), 7.87-7.83 (m,2H), 7.60 (m, 1H), 7.45 (m, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.87 (s, 1H),6.43 (s, 1H), 4.83 (d, J=4.5 Hz, 2H), 4.11 (s, 3H), 4.04 (s, 3H)

Example 27

¹H NMR (CDCl₃) δ8.75 (d, J=4.5 Hz, 2H), 8.19 (s, 1H), 7.63 (d, J=7.8 Hz,2H), 7.44-7.40 (m, 3H), 7.07 (m, 1H), 6.26 (s, 1H), 4.83 (d, J=5.1 Hz,2H)

Example 28

¹H NMR (CDCl₃) δ8.86 (s, 1H), 8.74 (m, 1H), 8.17 (s, 1H), 7.97 (m, 1H),7.66-7.63 (m, 2H), 7.62 (m, 1H), 7.41 (m, 1H), 7.07 (m, 1H), 6.35 (s,1H), 4.87 (d, J=6.0 Hz, 2H)

Example 30

¹H NMR (CDCl₃) δ8.16 (s, 1H), 7.66-7.62 (m, 2H), 7.41 (m, 1H), 7.33-7.22(m, 3H), 6.96 (t, J=6.0 Hz, 1H), 6.33 (s, 1H), 4.73 (d, J=6.0 Hz, 2H)

Example 31

¹H NMR (CDCl₃) δ8.13 (s, 1H), 7.66 (d, J=7.8 Hz, 2H), 7.45-7.40 (m, 2H),7.10-7.04 (m, 2H), 6.93 (t, J=6.6 Hz, 1H), 6.60 (s, 1H), 4.84 (d, J=6.6Hz, 2H)

Example 32

¹H NMR (CDCl₃) δ8.16 (s, 1H), 7.66-7.62 (m, 2H), 7.57-7.55 (m, 2H), 7.41(t, J=7.8 Hz, 1H), 7.31 (dd, J=7.8, 1.8 Hz, 1H), 6.99 (t, J=6.0 Hz, 1H),6.32 (s, 1H), 4.73 (d, J=6.0 Hz, 2H)

Example 40

¹H NMR (CDCl₃) δ8.01 (s, 1H), 7.31-7.24 (d, J=8.2 Hz, 1H), 6.72-6.64 (brt, J=5.4 Hz, 1H), 6.62-6.52 (m, 2H), 6.05-6.01 (s, 1H), 5.56-4.64 (d,J=6.0 Hz, 2H), 4.03-3.93 (s, 3H), 3.94-3.86 (s, 3H), 2.79-2.70 (d, J=8.1Hz, 2H), 2.02-1.66 (m, 6H), 1.43-1.22 (m, 3H), 1.20-1.02 (m, 2H)

Example 45

¹H NMR (CDCl₃) δ 8.73 (d, 2H), 8.54 (s, 1H), 7.41 (d, 2H), 7.02 (br,1H), 5.90 (s, 1H), 4.80 (s, 2H), 4.48 (q, 2H), 2.75 (s, 2H), 1.50 (t,2H), 1.06 (s, 9H);

Example 46

¹H NMR (CDCl₃) δ 8.79 (s, 1H), 8.72 (d, 1H), 8.14 (s, 1H), 7.84 (d, 1H),7.54-7.33 (m, 4H), 6.97 (t, 1H), 6.18 (s, 1H), 4.79 (d, 2H), 2.47 (s,3H)

Example 108

¹H NMR (CDCl₃) δ8.79 (s, 1H), 8.72 (d, J=3.0 Hz, 1H), 8.16 (s, 1H), 7.84(d, J=7.8 Hz, 1H), 7.74 (d, J=7.5 Hz, 2H), 7.55-7.35 (m, 3H), 6.92 (t,J=6.3 Hz, 1H), 6.42 (s, 1H), 4.81 (d, J=6.3 Hz, 2H)

Example 110

¹H NMR (CDCl₃) δ 8.18 (t, 1H), 8.03 (s, 1H), 7.44 (m, 1H), 7.30 (t, 1H),7.17 (q, 1H), 6.66 (s, 1H), 6.56 (br, 1H), 4.28 (d, 2H), 2.38 (s, 1H)

Example 111

¹H NMR (CDCl₃) δ8.72 (br, 1H), 8.59 (d, 1H), 8.11 (t, 1H), 8.06 (s, 1H),7.73 (d, 1H), 7.44 (d, 1H), 7.42-7.21 (m, 3H), 7.07 (q, 1H), 6.39 (d,1H), 5.21 (q, 1H), 4.16 (q, 2H), 3.08 (d, 2H), 1.22 (t, 3H)

Example 112

¹H NMR (CDCl₃) δ 8.22 (t, 1H), 8.15 (s, 1H), 7.51-7.33 (m, 7H), 7.21 (q,1H), 6.82 (d, 1H), 6.51 (s, 1H), 4.68 (q, 1H), 2.18 (m, 2H), 1.17 (t,3H)

Example 113

¹H NMR (CDCl₃) δ 8.22 (t, 1H), 8.14 (s, 1H), 7.51-7.33 (m, 7H), 7.21 (q,1H), 6.82 (d, 1H), 6.51 (s, 1H), 4.68 (q, 1H), 2.18 (m, 2H), 1.17 (t,3H)

Example 114

¹H NMR (CDCl₃) δ 8.81 (s, 1H), 8.75 (d, 1H), 8.21 (s, 1H), 7.84 (d, 1H),7.47 (q, 1H), 6.96 (s, 1H), 6.94 (t, 1H), 4.85 (d, 2H), 4.60 (q, 2H),1.58 (t, 3H)

Example 115

¹H NMR (CDCl₃) δ8.77 (s, 1H), 8.72 (d, 1H), 8.14 (s, 1H), 7.83 (d, 1H),7.65 (d, 1H), 7.44 (q, 1H), 7.80 (t, 1H), 7.6 (d, 1H), 6.18 (s, 1H),4.75 (d, 2H), 3.91 (s, 3H), 3.81 (s, 3H)

Example 116

¹H NMR (CDCl₃) δ8.67 (s, 1H), 8.55 (d, 1H), 8.50 (s, 1H), 7.92 (d, 1H),7.90 (d, 1H), 7.78 (t, 1H), 7.10 (d, 1H), 6.97 (s, 1H), 5.11 (s, 2H),3.77 (s, 6H)

Example 117

¹H NMR (CDCl₃) δ 8.38 (s, 1H), 8.30 (d, 1H), 8.17 (s, 1H), 7.52-7.37 (m,6H), 6.97 (t, 1H), 6.13 (s, 1H), 4.77 (d, 2H), 2.50 (s, 3H)

Example 118

¹H NMR (CDCl₃) δ 8.18 (t, 1H), 8.03 (s, 1H), 7.44 (m, 1H), 7.30 (t, 1H),7.17 (q, 1H), 6.66 (s, 1H), 6.56 (br, 1H), 4.28 (d, 2H), 2.38 (s, 1H);

Example 121

¹H NMR (CDCl₃) δ 8.6 (S, 1H), 8.15 (dt, 1H), 8.1 (s, 1H), 8.0 (d, 2H),7.5 (d, 2H), 7.4 (dd, 1H), 7.2 (d, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.6(s, 1H), 4.75 (d, 2H).

Example 126

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.5 (d, 1H), 7.42-7.35 (m,2H), 7.3-7.2 (m, 2H), 7.15 (dd, 1H), 7.1 (dd, 1H), 7.0 (t, 1H), 6.6 (s,1H), 4.8 (d, 2H).

Example 127

¹H NMR (CDCl₃) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.4 (dd, 1H), 7.3-7.25 (m,3H), 7.1 (dd, 1H), 6.9-6.85 (m, 2H), 6.7 (t, 1H), 6.6 (s, 1H), 4.6 (d,2H), 3.2 (m, 4H), 2.6 (m, 4H), 2.3 (s, 3H)

Example 128

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.1 (s, 1H), 8.0 (d, 2H), 7.5 (d, 2H),7.4 (m, 2H), 7.25 (d, 1H), 7.2 (s, 1H), 7.15 (dd, 1H), 7.0 (s, 1H), 6.8(t, 1H), 6.6 (s, 1H), 4.75 (d, 2H).

Example 129

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.05 (s, 1H), 8.0 (d, 2H), 7.5 (d, 2H),7.4 (m, 1H), 7.3 (dd, 1H), 7.15 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H), 4.75(d, 2H), 3.85 (s, 3H)

Example 130

¹H NMR (CDCl₃) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.4 (dd, 1H), 7.3 (dd, 1H),7.15 (dd, 1H), 6.8 (t, 1H), 6.4 (s, 1H), 4.2 (d, 2H), 3.8 (s, 3H).

Example 131

¹H NMR (CDCl₃) δ8.2 (dt, 1H), 8.0 (s, 1H), 7.4-7.15 (m, 3H), 6.7 (t,1H), 4.2 (q, 2H), 3.8 (dt, 2H), 2.8 (t, 2H), 1.2 (t, 3H)

Example 132

¹H NMR (CDCl₃) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.4-7.15 (m, 3H), 6.7 (t,1H), 4.2 (q, 2H), 3.8 (dt, 2H), 2.8 (t, 2H), 2.05 (m, 2H) 1.2 (t, 3H)

Example 133

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.3 (dd 1H),7.2 (dd, 1H), 6.5 (s, 1H), 6.4 (t, 1H), 3.7 (s, 3H), 3.5 (dd, 2H), 2.4(t, 2H), 1.8 (m, 4H)

Example 134

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.95 (d, 2H), 7.6 (d, 2H),7.4 (m, 1H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H), 4.8(d, 2H), 3.0 (s, 3H)

Example 135

¹H NMR (DMSO d6) δ 9.1 (bs, 2H), 8.4 (s, 1H), 8.0 (t, 1H), 7.85 (d, 2H),7.7 (d, 2H), 7.6 (m, 1H), 7.4 (m, 2H), 6.6 (s, 1H), 4.8 (bs, 2H)

Example 136

¹H NMR (CDCl₃) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.25 (dd, 1H),7.15 (dd, 1H), 6.9 (m, 3H), 6.7 (t, 1H), 6.5 (s, 1H), 4.5 (d, 2H), 4.2(s, 4H)

Example 137

¹H NMR (CDCl₃) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.3 (dd, 1H),7.2 (dd, 1H), 6.9 (dd, 1H), 6.8 (t, 1H), 6.7 (m, 1H), 6.6 (s, 1H), 5.3(s, 2H), 4.85 (s, 2H), 4.6 (d, 2H).

Example 138

¹H NMR (CDCl₃) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.9 (d, 1H), 7.8 (d, 1H),7.4 (m, 2H), 7.3 (dd, 1H), 7.1 (dd, 1H), 6.9 (t, 1H), 6.6 (s, 1H), 4.8(d, 2H)

Example 139

¹H NMR (CDCl₃) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.3 (m, 2H),7.2 (dd, 1H), 7.1 (dd, 1H), 6.8 (d, 1H), 6.7 (t, 1H), 6.6 (s, 1H), 4.6(m, 4H), 3.2 (t, 2H)

Example 140

¹H NMR (CDCl₃) δ 8.45 (s, 1H), 8.2 (dt, 1H), 8.0 (s, 1H), 7.7 (dd, 1H),7.4-7.3 (m, 3H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.6 (s, 1H), 4.7 (d, 2H)

Example 141

¹H NMR (CDCl₃) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.45-7.1 (m, 7H), 6.6 (s,1H), 4.4 (dt, 2H), 2.6 (t, 2H), 1.8 (m, 2H), 1.4 (m, 2H)

Example 171

¹H NMR (CD₃OD) δ 8.41 (s, 1H), 8.25 (d, J=6.3 Hz, 1H), 8.15 (s, 1H),7.67 (d, J=7.8 Hz, 2H), 7.55-7.48 (m, 2H), 7.45 (dd, J=7.5, 1.2 Hz, 1H),7.34 (dd, J=7.5, 1.8 Hz, 1H), 6.28 (s, 1H), 4.79 (s, 2H).

Example 172

¹H NMR (CDCl₃) δ 8.64 (s, 1H), 7.68-7.64 (m, 2H), 7.52 (m, 1H), 7.43 (t,J=7.8 Hz, 1H), 6.89 (t, J=6.0 Hz, 1H), 6.51 (s, 1H), 6.48 (m, 2H), 4.74(d, J=6.0 Hz, 2H).

Example 173

¹H NMR (DMSO-d₆) δ 8.86 (s, 1H), 8.46 (s, 1H), 8.32-8.28 (m, 2H), 7.97(m, 1H), 7.87 (m, 1H), 7.52 (m, 1H), 7.35-7.24 (m, 2H), 6.57 (s, 1H),6.46 (m, 1H), 3.65 (m, 4H).

Example 174

¹H NMR (CDCl₃) d 8.37 (s, 1H), 8.16 (t, J=7.5 Hz, 1H), 7.45-7.35 (m,1H), 7.32-7.20 (m, 3H), 7.17-7.07 (m, 1H), 6.92 (t, J=6 Hz, 1H), 6.48(s, 1H), 4.65 (d, 2H), 2.50 (s, 3H).

Example 175

¹H NMR (CDCl₃) d 8.16 (t, J=9 Hz, 1H), 8.00 (s, 1H), 7.49 (d, J=9 Hz,1H), 7.46-7.36 (m, 1H), 7.18-7.08 (m, 1H), 7.00 (d, J=9 Hz, 1H),6.62-6.50 (m, 2H), 2.60 (s, 3H), 2.55 (s, 3H).

Example 176

¹H NMR (CDCl₃) d 8.15 (t, J=9 Hz, 1H), 8.00 (s, 1H), 7.45-7.35 (m, 1H),7.32-7.20 (m, 1H), 7.20-7.05 (m, 3H), 6.80 (t, 1H), 6.50 (s, 1H), 4.65(d, 2H), 2.65 (s, 3H), 2.50 (s, 3H).

Example 177

¹H NMR (CDCl₃) d 8.20 (t, 1H), 7.90 (s, 1H), 7.50-7.05 (m, 8H), 6.80 (s,1H), 5.05-4.90 (m, 2H), 3.80 (d, 1H), 3.45 (d, 1H), 3.00 (dd, 1H), 2.90(dd, 1H), 2.50 (s, 3H).

Example 181

¹H NMR (300 MHz, CDCl₃) □ 8.41 (s, 1H), 8.28-8.23 (d, 1H), 8.15 (s, 1H),7.69-7.60 (d, 1H), 7.62-7.50 (m, 3H), 7.50-7.47 (dd, 1H), 6.35 (s, 1H),5.36 (s, 1H), 4.80 (s, 2H).

Example 184

¹H NMR (300 MHz, CDCl₃)

8.96-8.90 (s, 1H), 8.08 (s, 1H), 8.04 (d, 1H), 7.72 (d, 1H), 7.70-7.61(dd, 1H), 7.24-7.20 (dd, 1H), 6.92-6.84 (t, 1H), 6.36 (s, 1H), 4.96-4.89(d, 2H).

Example 186

¹H NMR (300 MHz, CDCl₃)

8.96-8.90 (s, 1H), 8.08 (s, 1H), 8.44 (s, 1H), 8.27-8.24 (d, 1H), 8.02(s, 1H), 7.78-7.76 (d, 1H), 7.73-7.70 (d, 1H), 7.58-7.51 (m, 2H),7.13-7.08 (dd, 1H), 5.51 (s, 2H).

Example 195

¹H NMR (CD₃OD) δ8.40 (s, 1H), 8.27 (d, 1H), 8.03 (s, 1H), 7.75-7.50 (m,2H), 6.10 (s, 1H), 4.76 (s, 2H), 4.05 (m, 2H), 3.88 (m, 2H), 3.52 (m,1H), 2.33 (m, 1H), 2.20 (m, 1H).

Example 196

¹H NMR (CD₃OD) δ 8.73 (d, 1H), 8.58 (q, 1H), 8.12 (s, 1H), 8.00 (d, 1H),7.54 (q, 1H), 6.19 (s, 1H), 4.86 (s, 2H), 4.22-4.08 (m, 2H), 4.03-3.93(m, 2H), 3.63 (m, 1H), 2.50-2.39 (m, 1H), 2.32-2.21 (m, 1H).

Example 197

¹H NMR (CD₃OD) δ8.73 (d, 1H), 8.58 (q, 1H), 8.12 (s, 1H), 8.00 (d, 1H),7.54 (q, 1H), 6.19 (s, 1H), 4.86 (s, 2H), 4.22-4.08 (m, 2H), 4.03-3.93(m, 2H), 3.63 (m, 1H), 2.50-2.39 (m, 1H), 2.32-2.21 (m, 1H).

Example 199

¹H NMR (300 MHz, CDCl₃)

8.29 (s, 1H), 8.15 (br s, 1H), 7.95 (s, 1H), 7.28 (d, 1H), 7.05-6.95(appt t, 1H), 5.70 (s, 1H), 4.62 (d, 2H), 2.90 (m, 1H), 2.30 (m, 1H),1.9-1.2 (m, 8H), 0.65 (d, 3H).

Example 200

¹H NMR (300 MHz, CDCl₃)

18.71 (s, 2H), 8.00 (s, 1H), 6.13 (s, 1H), 3.59 (s, 2H), 3.01-2.58 (m,1H), 2.51-2.45 (m, 1H), 2.44-2.30 (m, 1H), 2.20 (s, 3H), 2.09-1.95 (m,2H), 1.85-1.70 (m, 2H), 0.80-0.76 (d, 3H).

Example 203

¹H NMR (300 MHz, CDCl₃)

18.10 (s, 1H), 8.08 (s, 1H), 6.27 (s, 2H), 4.95 (s, 2H), 3.00-2.90 (dd,2H), 2.60 (m, 2H), 2.48 (br s, 1H), 2.39 (s, 3h), 2.25 m, 1H), 1.95-1.70(m, 3H).

Example 211

To a solution of the compound prepared in Example 156 (100 mg, 0.23mmol) in dry THF (4 mL) was added LiAlH₄ (1.0 M in THF, 0.110 mL, 0.110mmol) at 0° C. under N₂. The mixture was stirred at 0° C. for 1 hr,warmed to 25° C., then additional LiAlH₄ (1.0 M in THF, 0.400 mL) wasadded, the mixture was stirred for 20 min and then quenched with MeOH(2.0 mL). The solvent was evaporated and the crude product was purifiedby flash chromatography using 10:1 CH₂Cl₂:MeOH as eluent. White solid(46 mg, 49%) was obtained. LCMS: M⁺=416. Mp=71-72° C.

Example 212

To a solution of the compound prepared in Example 156 (70 mg, 0.16 mmol)in dry THF (3 mL) was added MeMgBr (3.0 M in Et₂O, 1.10 mL, 3.20 mmol)under N₂. The mixture was stirred at 25° C. for 45 min and then quenchedwith saturated aqueous NH₄Cl (5.0 mL). The mixture was poured intosaturated aqueous NH₄Cl (30 mL) and extracted with CH₂Cl₂ (3×20 mL). Theextracts were dried over Na₂SO₄ and filtered. The solvent was evaporatedand the crude product was purified by flash chromatography using 20:1CH₂Cl₂:MeOH as eluent. White solid (25 mg, 36%) was obtained. LCMS:M⁺=444. Mp=76-80° C.

Example 213

Anhydrous DMF (40 mL) was added under N₂ to the compound prepared inPreparative Example 174 (2.50 g, 8.65 mmol) and 60% NaH in mineral oil(346 mg, 8.65 mmol). The mixture was stirred at 25° C. for 1 hr, then2-chloro-5-chloromethylpyridine N-oxide (1.54 g, 8.65 mmol) in anhydrousDMF (20 mL) was added slowly. The mixture was stirred at 25° C. for 18hr, the solvent was evaporated and the crude product was purified byflash chromatography using 30:1 CH₂Cl₂:MeOH as eluent. So obtained solidwas triturated by 50 mL of 1:1 EtOAc:hexane. Pale yellow solid (1.25 g,34%) was obtained. LCMS: MH⁺=432. Mp=224-226° C.

Examples 214-217

By essentially the same procedure set forth in Example 213 combining thecompounds shown in Column 2 of Table 19 with compounds in Column 3 ofTable 19, the compounds shown in Column 3 of Table 19 were prepared.TABLE 19 Ex. Column 2 Column 3 Column 4 CMPD 214

LCMS: MH⁺ = 380: mp = ° C. 215

LCMS: MH⁺ = 450: mp = 218-222° C. 216

LCMS: MH⁺ = 466; mp = 126-128° C. 217

LCMS: M⁺ = 523

Example 218

CF₃CH₂OH (3.0 mL) was added under N₂ to 60% NaH in mineral oil (40 mg,1.0 mmol), the mixture was stirred for 20 min, then the product preparedin Example 213 (50 mg, 0.12 mmol) was added. The mixture was refluxedfor 20 hr, the solvent was evaporated, and the residue was purified byflash chromatography using 20:1 CH₂Cl₂:MeOH as eluent to yield paleyellow solid (35 mg, 61%). LCMS: M2H⁺=496. Mp=208-210° C.

Examples 219-225

By essentially the same procedure set forth in Example 218 combining thecompounds shown in Column 1 of Table 20 with the appropriate alcohol,the compounds shown in Column 2 of Table 20 were prepared. TABLE 20 Ex.Column 1 Column 2 Data 219

LCMS: M⁺ = 426; mp = 126-128° C. 220

LCMS: M⁺ = 483; mp = 89-91° C. 221

LCMS: M2H⁺ = 442; mp = 112-114° C. 222

LCMS: MH⁺ = 462; mp = 121-123° C. 223

LCMS: MH⁺ = 444; mp = 112-114° C. 224

LCMS: M⁺ = 376; mp = ° C. 225

LCMS: MH⁺ =; mp = ° C.

Examples 226

A mixture of the product prepared in Example 213 (100 mg, 0.23 mmol) andKOH (95 mg, 1.70 mmol) in 1,2-dimethoxyethane (3 mL) and H₂O (1.5 mL)was refluxed under N₂ for 20 hr, quenched with acetic acid (0.30 mL),and the solvent was evaporated. The residue was suspended in H₂O (15mL), filtered and the solid washed with H₂O (15 mL) and Et₂O (10 mL).Then it was mixed with CH₂Cl₂ (2 mL) and Et₂O (2 mL) and filtered. Et₂O(5 mL) was added to the filtrate and the mixture was allowed to standovernight. The solid was removed by filtration, washed with Et₂O andthen dissolved in MeOH (5 mL). The solution was filtered and the solventfrom the filtrate was evaporated. Off-white solid (5 mg, 5%) wasobtained. LCMS: M⁺=412. Mp=206-208° C.

Example 227

A mixture of the product prepared in Example 213 (129 mg, 0.30 mmol),N,N-dimethylethylenediamine (0.165 mL, 1.50 mmol), anddiisopropylethylamine (0.10 mL) in anhydrous N-methylpyrrolidinone (1.0mL) was stirred at 100° C. for 24 hr. The solvent was evaporated, andthe residue was purified by flash chromatography using 20:1 CH₂Cl₂:7NNH₃ in MeOH as eluent to yield pale yellow solid (110 mg, 76%). LCMS:M⁺=482. Mp=76-78° C.

Examples 228-233

By essentially the same procedure set forth in Example 227 combining thecompounds shown in Column 1 of Table 21 with the appropriate amine, thecompounds shown in Column 2 of Table 21 were prepared. TABLE 21 Ex.Column 1 Column 2 Data 228

LCMS: M2H⁺ = 467; mp 126-128= ° C. 229

LCMS: M⁺ = 481; mp = 128-130° C. 230

LCMS: M⁺ = 494; mp = 108- 110° C. 231

LCMS: M2H⁺ = 482; mp = 129-133° C. 232

LCMS: M2H⁺ = 482; mp = 124-126° C. 233

LCMS: M2H⁺ = 471; mp = 88-90° C.

Examples 234

A mixture of the product prepared in Example 213 (80 mg, 0.19 mmol) and2.0 M methylamine in THF was stirred in a closed pressure vessel at 50°C. for 72 hr. The solvent was evaporated, and the residue was purifiedby flash chromatography using 10:1 CH₂Cl₂: MeOH as eluent to yield paleyellow solid (40 mg, 51%). LCMS: M2H⁺=427. Mp=217-219° C.

Example 235

By essentially the same procedure set forth in Example 234, the compoundshown above was prepared. LCMS: M2H⁺=441. Mp=98-101° C.

Example 236

The compound prepared in Preparative Example 174 (140 mg, 0.48 mmol) andthe aldehyde (71 mg, 0.58 mmol) were stirred in anhydrous THF (4 mL) at50° C. under N₂. Ti(OiPr)₄ (0.574 mL, 1.92 mmol) was added, the mixturewas stirred at 50° C. 3 hr, and cooled to 25° C. NaBH₃CN (181 mg, 2.88mmol) was added, the mixture was stirred for 2 more hr, then poured into10% aqueous Na₂CO₃ (100 mL), and extracted with CH₂Cl₂ (3×50 mL).Combined extracts were dried over Na₂SO₄, filtered, and the solvent wasevaporated. The residue was purified by flash chromatography using 15:1CH₂Cl₂:MeOH as eluent to yield pale yellow solid (40 mg, 21%). LCMS:MH⁺=398. Mp>230° C.

Examples 237-256

By essentially the same procedure set forth in Example 236 combining thecompounds shown in Column 2 and 3 of Table 22, the compounds shown inColumn 4 of Table 22 were prepared. TABLE 22 Ex. Column 2 Column 3Column 4 Data 237

LCMS: M⁺ = 381; mp > 200° C. 238

LCMS: M⁺ = 387; mp = ° C. 239

LCMS: MH⁺ = 413; mp = 157- 159° C. 240

LCMS: M2H⁺ = 419; mp = 77- 79° C. 241

LCMS: M2H⁺ = 385; mp = 214-216° C. 242

LCMS: MH⁺ =; mp = ° C. 243

LCMS: M⁺ = 416; mp = 80-82° C. 244

245

246

LCMS: M⁺ = 452; mp = 54-56° C. 247

LCMS: MH⁺ = 401; mp > 200° C. 248

LCMS: M2H⁺ = 474; mp > 200.0.° C. dec. 249

LCMS: MH⁺ = 377; mp = 65-67° C. 250

LCMS: M2H⁺ = 421; mp = 87-93° C. 251

LCMS: MH⁺ = 361; mp > 225° C. 252

LCMS: MH⁺ = 346; mp = 270-271° C. 253

LCMS: MH⁺ = 402; mp = 250-255° C. 254

LCMS: MH⁺ = 416; mp = 210-215° C. 255

LCMS: MH⁺ = 428; mp = 145° C. 256

LCMS: MH⁺ =; mp = ° C.

Example 257

A mixture of the compound prepared in Example 242 (100 mg, 0.24 mmol),conc. aqueous HCl (1.0 mL) and acetic acid (2.0 mL) were stirred at 100°C. under N₂ for 2 hr, then poured onto Na₂CO₃ (15 g), and extracted with1:1 acetone:CH₂Cl₂ (3×30 mL). Combined extracts were filtered, and thesolvent was evaporated. The residue was purified by flash chromatographyusing 10:1 CH₂Cl₂:MeOH as eluent to yield pale yellow solid (36 mg,37%). LCMS: M2H⁺=398.

Examples 58-260

By essentially the same procedure set forth in Example 257 starting fromthe compounds shown in Column 1 of Table 23, the compounds shown inColumn 2 of Table 23 were prepared. TABLE 23 Ex. Column 1 Column 2 Data258

LCMS: M⁺ = 402; mp = 229-231° C. 259

LCMS: MH⁺ = 416; mp = 215-218° C. 260

LCMS: M2H⁺ = 398; mp > 230° C.

Example 261

To a stirred solution of the compound prepared in Example 239 (41 mg,0.10 mmol) in CH₂Cl₂ was added 1.0 M BBr₃ (0.30 mL, 0.30 mmol) in CH₂Cl₂at −78° C. The mixture was stirred at −78° C. for 5 min, then at 24° C.for 3 hr, then MeOH (2.0 mL) was added and the mixture was stirred for10 min. The solvent was evaporated and the residue was purified by flashchromatography using 5:1:0.1 CH₂Cl₂:MeOH:conc. NH₄OH as eluent to yieldwhite solid (39 mg, 99%). LCMS: M⁺=397. Mp>230° C.

Example 262

A mixture of the product prepared in Example 217 (40 mg, 0.077 mmol) and5.0 M aqueous NaOH (0.8 mL) in MeOH (3.0 mL) was refluxed under N₂ for 1hr. NaHCO₃ (700 mg) was added, the solvent evaporated, and the residuewas purified by flash chromatography using 10:1:0.1 CH₂Cl₂:MeOH:conc.NH₄OH as eluent to yield white solid (10 mg, 35%). LCMS: M2H⁺=371.Mp=237-239° C.

Examples 263-264

By essentially the same procedure set forth in Example 262 starting fromthe compounds shown in Column 1 of Table 24, the compounds shown inColumn 2 of Table 24 were prepared. TABLE 24 Ex. Column 1 Column 2 Data263

LCMS: M2H⁺ = 370; mp = 166-168° C. 264

LCMS: M2H⁺ = 371; mp = 180-182° C.

Example 265

TFA (0.5 mL) was added to a solution of the compound prepared inPreparative Example 197 (0.08 g, 0.16 mmol) in CH₂Cl₂ (2.0 mL) at 0° C.and the resulting solution stirred 2.5 hours and stored at 4° C.overnight at which time additional TFA (0.5 mL) was added. The resultingsolution was stirred 4 hours and concentrated in vacuo. The residue wasneutralized with 1N NaOH and extracted with CH₂Cl₂. The combinedorganics were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The crude product was purified by flash chromatographyusing a 2.5% (10% NH₄OH in MeOH) in CH₂Cl₂ solution as eluent (0.009 g,15% yield). LCMS: MH⁺=396; mp=53-54° C.

Example 266

A solution of the compound prepared in Preparative Example 182 (26 mg,0.070 mmol) and potassium thiocyanate (13 mg, 0.14 mmol) in MeOH (1 mL)was cooled in a cold water bath. To it was added a solution of bromine(22 mg, 0.14 mmol) in MeOH (0.7 mL) dropwise. The resulting reactionmixture was stirred for 4 h at room temperature and the volatiles wereremoved under reduced pressure. The residue obtained was suspended in asmall amount of CH₂Cl₂. The potassium bromide was filtered off and pH ofthe filtrate was adjusted to about 7 by the addition of aqueous ammonia.It was concentrated under reduced pressure and the residual oil waspurified by preparative thin-layer chromatography using 15% MeOH inCH₂Cl₂ as eluent (26 mg, 87% yield). ¹H NMR (CDCl₃) δ 8.75 (d, J=4.2 Hz,2H), 8.38 (s, 1H), 7.68-7.64 (m, 2H), 7.46-7.39 (m, 3H), 7.22 (t, J=6.3Hz, 1H), 6.43 (s, 1H), 4.84 (d, J=6.3 Hz, 2H); LCMS: MH⁺=427.

Example 267

Boron tribromide (1 M in CH₂Cl₂, 0.60 mL, 0.60 mmol) was added dropwiseto an ice-cold stirred solution of the compound prepared in Example 24(50 mg, 0.12 mmol) in CH₂Cl₂ (1.5 mL) under an argon atmosphere. Theresulting reaction mixture was stirred at 0° C. for 30 minutes, allowedto warm up to room temperature, and stirred overnight. The mixture wasquenched by the addition of a small amount of water and extracted withCH₂Cl₂. The organic layer was dried over magnesium sulfate andconcentrated in vacuo (45 mg, 94% yield). ¹H NMR (CD₃OD) δ 9.16 (s, 1H),8.95 (s, 1H), 8.88 (d, J=8.1 Hz, 1H), 8.24 (t, J=6.9 Hz, 1H), 8.18 (s,1H), 7.95 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.00-6.96 (m, 2H),6.86 (s, 1H), 5.28 (s, 2H); LCMS: MH⁺=396.

Example 268

A solution of the compound from Preparative Example 184 (0.05 g, 0.15mmol), N-methylpiperazine (20 μL, 1.2 eq.) and iPr₂Et (52 μL, 2.0 eq.)in dioxane (1 mL) was heated to 70° C. overnight. The reaction mixturewas cooled to room temperature and diluted with H₂O and saturatedNaHCO₃. The resulting mixture was extracted with CH₂Cl₂, the combinedorganics dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude product was purified by Preparative TLC using a 5%(10% NH₄OH in MeOH) in CH₂Cl₂ solution as eluent (0.028 g, 47% yield).MS: MH⁺=402. mp=210° C. (dec.)

Examples 269-275

By essentially the same procedure set forth in Example 268 onlysubstituting the amine in Column 2 of Table 25 and the chlorides inColumn 3 of Table 25, the compounds shown in Column 4 of Table 25 areprepared: TABLE 25 Ex. Column 2 Column 3 Column 4 CMPD 269

MS: MH⁺ = 387 m.p. 182-183° C. 270

MS: MH⁺ = 373 m.p. 190-191° C. 271

MS: MH⁺ = 403 m.p. 227-230° C. 272

MS: MH⁺ = 388 m.p. 198-201° C. 273

MS: MH⁺ = 430 m.p. 100-103° C. 274

MS: MH⁺ = 456 m.p. 175-178° C. 275

MS: MH⁺ = 403 m.p. 218° C.

Example 276

Step A:

4-Fluorophenyl magnesium bromide (0.68 mL, 1.2 eq.) was added to thecompound prepared in Preparative Example 193 (0.20 g, 0.55 mmol) andPdCl₂(dppf)₂ (0.037 g, 10 mol %) in THF and the resulting solution wasstirred at room temperature 72 hours. The reaction mixture was dilutewith saturated NH₄Cl and extracted with EtOAc. The combined organicswere washed with saturated NaCl, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by flash chromatographyusing neat EtOAc as eluent (0.15 g, 65% yield). MS: MH⁺=420.Step B:

By essentially the same procedure set forth in Preparative Example 127only substituting the compound prepared in Example 276, Step A, theabove compound was prepared (0.17 g, 94% yield).Step C:

By essentially the same procedure set forth in Preparative Example 200only substituting the compound prepared in Example 276, Step B, theabove compound was prepared (0.1 g, 100% yield).Step D:

By essentially the same procedure set forth in Example 265 onlysubstituting the compound prepared in Example 276, Step C, the abovecompound was prepared (0.049 g, 62% yield). MS: MH⁺=414; mp=110-115° C.

Example 277

Step A:

Pd(PPh₃)₄ (0.065 g, 10 mol %) was added to 3-cyanophenyl zinc iodide(2.2 mL, 0.5 M solution in THF, 2 eq.) and the compound prepared inPreparative Example 193 (0.2 g, 0.56 mmol) in DMF (2.0 mL) and theresulting solution heated to 80° C. g for 144 hours. The reactionmixture was cooled to room temperature, diluted with saturated NH₄Cl andextracted with EtOAc. The combined organics were washed with H₂O andbrine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude product was purified by flash chromatography using aneat EtOAC solution as eluent (0.07 g, 29% yield). MS: MH⁺=427.Step B Through Step D:

By essentially the same procedures set forth in Example 276, Step Bthrough Step D, the above compound was prepared (0.023 g, 53% yield).MS: MH⁺=421; mp=230° C. (dec.)

Example 278

By essentially the same procedure set forth in Example 276 onlysubstituting the appropriate cyclopropylmagnesium bromide in Step A, thecompound was prepared. MS: MH⁺=372; m.p.=96-98° C.

Example 279

The palladium-catalyzed zinc cross-coupling reaction was carried out ina manner similar to the procedure described in J. Org. Chem. (1999),453. A solution of the chloropyrazolopyrimidine (200 mg, 0.458 mmol),Pd(PPh₃)₄ (53 mg, 0.046 mmol), and exo-2-norbonylzinc bromide (0.5 M inTHF, 0.95 mL, 0.47 mmol) in DMF (2 mL) was refluxed at 100° C. (oil bathtemp.) overnight. The reaction mixture was quenched with half-saturatedNH₄Cl and extracted with CH₂Cl₂. The organic phase was dried over MgSO₄and concentrated under reduced pressure. The residue was purified byflash chromatography using a 50% EtOAc in hexanes solution as eluent. Asolution of the obtained N-Boc-protected product (121 mg, 53% yield,LCMS: MH⁺=498) and TFA (1 mL) in CH₂Cl₂ (2 mL) was stirred at roomtemperature for 2 hr. The volatiles were removed under reduced pressure.The residue was dissolved in CH₂Cl₂, neutralized with saturated NaHCO₃,and extracted with CH₂Cl₂. The organic phase was dried over MgSO₄ andconcentrated in vacuo (96 mg, 99% yield). LCMS: MH⁺=398; ¹H NMR (CDCl₃)δ 8.78 (s, 1H), 8.71 (d, J=4.2 Hz, 1H), 8.04 (d, J=3.9 Hz, 1H), 7.80 (d,J=7.8 Hz, 1H), 7.44 (m, 1H), 6.73 (m, 1H), 5.98 (d, J=7.5 Hz, 1H), 4.74(d, J=5.4 Hz, 2H), 3.40-1.00 (m, 11H).

Examples 280-294

By following essentially the same procedure set forth in Example 279only substituting the chlorides shown in Column 2 of Table 26 and theorganozinc reagents shown in Column 3 of Table 26, the compounds inColumn 4 of Table 26 were prepared: TABLE 26 Ex. Column 2 Column 3Column 4 Data 280

LCMS: MH⁺ = 395 281

LCMS: MH⁺ = 400 282

LCMS: MH⁺ = 412 283

LCMS: MH⁺ = 452 284

LCMS: MH⁺ = 422 285

LCMS: MH⁺ = 408 286

LCMS: MH⁺ = 404 287

LCMS: MH⁺ = 404 288

LCMS: MH⁺ = 408 289

LCMS: MH⁺ = 386 290

LCMS: MH⁺ = 464 291

LCMS: MH⁺ = 480 292

LCMS: MH⁺ = 424 293

LCMS: MH⁺ = 424 294

LCMS: MH⁺ = 426Additional data for select compounds is shown below.

Example 280

¹H NMR (CDCl₃) δ 8.65 (s, 1H), 8.57 (d, J=4.2 Hz, 1H), 8.50 (d, J=4.5Hz, 1H), 8.01 (s, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H),7.31-7.22 (m, 2H), 6.77 (m, 2H), 4.71 (d, J=5.4 Hz, 2H), 2.68 (s, 3H).

Example 281

¹H NMR (CDCl₃) δ8.80 (s, 1H), 8.72 (d, J=4.8 Hz, 1H), 8.08 (s, 1H),7.85-7.40 (m, 3H), 7.02 (d, J=5.1 Hz, 1H), 6.90 (t, J=6.0 Hz, 1H), 6.29(s, 1H), 4.79 (d, J=6.0 Hz, 2H), 2.61 (s, 3H).

Example 282

¹H NMR (CDCl₃) δ8.67 (s, 1H), 8.61 (d, J=3.9 Hz, 1H), 8.03 (s, 1H),7.72-7.31 (m, 3H), 7.22-7.00 (m, 2H), 6.81 (t, J=6.0 Hz, 1H), 6.03 (s,1H), 4.68 (d, J=6.0 Hz, 2H), 2.28 (s, 3H).

Example 283

¹H NMR (CDCl₃) δ 8.68 (s, 1H), 8.63 (d, J=4.0 Hz, 1H), 8.00 (s, 1H),7.80-7.72 (m, 2H), 7.54-7.47 (m, 3H), 7.35 (m, 1H), 6.74 (t, J=6.0 Hz,1H), 6.19 (s, 1H), 4.67 (d, J=6.0 Hz, 2H), 4.21 (q, J=7.2 Hz, 2H), 1.13(t, J=7.2 Hz, 3H).

Example 284

¹H NMR (CDCl₃) δ 7.97 (s, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.33-7.15 (m,5H), 6.73 (t, J=5.4 Hz, 1H), 5.99 (s, 1H), 4.61 (d, J=5.4 Hz, 2H), 3.09(sept, J=6.9 Hz, 1H), 1.11 (d, J=6.9 Hz, 6H).

Example 285

¹H NMR (CDCl₃) δ8.56-8.55 (m, 2H), 7.94 (s, 1H), 7.54 (m, 1H), 7.30-7.22(m, 6H), 6.59 (t, J=5.7 Hz, 1H), 5.66 (s, 1H), 4.47 (d, J=5.7 Hz, 2H),4.26 (q, J=7.2 Hz, 1H), 1.68 (d, J=7.2 Hz, 3H).

Example 286

¹H NMR (CDCl₃) δ8.67 (m, 2H), 7.94 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.34(m, 1H), 6.63 (t, J=5.7 Hz, 1H), 5.87 (s, 1H), 4.62 (d, J=5.7 Hz, 2H),3.64 (s, 3H), 3.13 (m, 2H), 2.82 (m, 1H), 1.22 (m, 3H).

Example 287

¹H NMR (CDCl₃) δ8.66 (m, 2H), 7.94 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.34(m, 1H), 6.62 (t, J=6.0 Hz, 1H), 5.87 (s, 1H), 4.62 (d, J=6.0 Hz, 2H),3.64 (s, 3H), 3.13 (m, 2H), 2.81 (m, 1H), 1.22 (m, 3H).

Example 288

¹H NMR (CDCl₃) δ 8.64 (s, 1H), 8.60 (d, J=3.6 Hz, 1H), 8.04 (s, 1H),7.68 (m, 1H), 7.31 (m, 1H), 7.16 (m, 1H), 7.07-7.05 (m, 2H), 6.80 (t,J=6.3 Hz, 1H), 5.93 (s, 1H), 4.64 (d, J=6.3 Hz, 2H), 2.08 (s, 6H).

Example 289

¹H NMR (CDCl₃) δ8.72 (s, 1H), 8.62 (d, J=4.8 Hz, 1H), 7.99-7.97 (m, 2H),7.73-7.69 (m, 2H), 7.40-7.33 (m, 2H), 6.67 (t, J=6.0 Hz, 1H), 6.29 (s,1H), 4.71 (d, J=6.0 Hz, 2H).

Example 290

¹H NMR (CDCl₃) δ8.73 (s, 1H), 8.62 (d, J=4.5 Hz, 1H), 8.01 (s, 1H), 7.76(m, 1H), 7.41 (d, J=5.1 Hz, 1H), 7.34 (dd, J=8.1, 5.1 Hz, 1H), 7.05 (d,J=5.1 Hz, 1H), 7.01 (s, 1H), 6.79 (t, J=6.0 Hz, 1H), 4.74 (d, J=6.0 Hz,2H).

Example 291

¹H NMR (DMSO-d₆) δ9.12 (s, 1H), 8.40 (s, 1H), 8.33 (s, 1H), 8.13 (m,1H), 7.82 (d, J=5.1 Hz, 1H), 7.40-7.39 (m, 2H), 7.22 (d, J=5.1 Hz, 1H),6.86 (s, 1H), 4.86 (s, 2H).

Example 292

¹H NMR (CDCl₃) δ8.23 (s, 1H), 8.16 (d, J=6.0 Hz, 1H), 8.06 (s, 1H),7.31-7.05 (m, 5H), 6.86 (m, 1H), 5.87 (s, 1H), 4.62 (d, J=6.3 Hz, 2H),2.09 (s, 6H).

Example 293

¹H NMR (CDCl₃) δ8.14 (s, 1H), 8.12 (d, J=6.3 Hz, 1H), 7.94 (s, 1H),7.29-7.16 (m, 6H), 7.07 (m, 1H), 6.78 (t, J=6.0 Hz, 1H), 5.54 (s, 1H),4.44 (d, J=6.0 Hz, 2H), 4.24 (t, J=7.2 Hz, 1H), 1.68 (d, J=7.2 Hz, 3H).

Example 294

¹H NMR (CDCl₃) δ8.67 (s, 1H), 8.59 (d, J=4.8 Hz, 1H), 8.01 (s, 1H), 7.71(m, 1H), 7.52 (dd, J=7.8, 1.8 Hz, 1H), 7.40-7.19 (m, 4H), 6.78 (t, J=6.0Hz, 1H), 6.32 (s, 1H), 4.67 (d, J=6.0 Hz, 2H), 2.38 (s, 3H).

Example 295

To a suspension of lithium aluminum hydride (10 mg, 0.26 mmol) inanhydrous THF (2 mL) at 0° C. was added dropwise a solution of thecompound prepared in Example 283 (20 mg, 0.044 mmol) in anhydrous THF (2mL). The resulting mixture was refluxed for 1 hr and stirred at roomtemperature overnight, neutralized with dilute sulfuric acid, andextracted with EtOAc. The organic phase was dried over MgSO₄ andconcentrated under reduced pressure. The crude product was purified bypreparative thin-layer chromatography using a 5% MeOH in EtOAc solutionas eluent (15 mg, 83% yield). LCMS: MH⁺=410; ¹H NMR (CDCl₃) δ 8.69 (s,1H), 8.61 (d, J=3.9 Hz, 1H), 8.05 (d, J=2.1 Hz, 1H), 7.74 (d, J=7.8 Hz,1H), 7.52-7.31 (m, 5H), 6.97 (t, J=6.3 Hz, 1H), 6.55 (d, J=2.7 Hz, 1H),6.20 (s, 1H), 4.71 (d, J=6.3 Hz, 2H), 4.52 (s, 2H).

Example 296

To a solution of the N-Boc-protected compound prepared in Example 294(45 mg, 0.085 mmol) in CH₂Cl₂ (4 mL) at −50° C. was added m-CPBA (18 mg,0.10 mmol). After stirring for 1 hr at −50° C. more MCPBA (4 mg, 0.02mmol) was added. The mixture was stirred for a further 2 hr, dilutedwith CH₂Cl₂ (20 mL), and washed with saturated NaHCO₃ (20 mL). Theorganic phase was dried over MgSO₄ and concentrated under reducedpressure. The residue was purified by preparative thin-layerchromatography using a 2.5% MeOH in CH₂Cl₂ solution as eluent. Asolution of the obtained N-Boc-protected product (37 mg, 80% yield,LCMS: MH⁺=542) and TFA (1 mL) in CH₂Cl₂ (2 mL) was stirred at roomtemperature for 2 hr. The volatiles were removed under reduced pressure.The residue was dissolved in CH₂Cl₂, neutralized with saturated NaHCO₃,and extracted with CH₂Cl₂. The organic phase was dried over MgSO₄ andconcentrated under reduced pressure. The crude product was purified bypreparative thin-layer chromatography using a 5% MeOH in EtOAc solutionas eluent (26 mg, 89% yield). LCMS: MH⁺=442; ¹H NMR (CDCl₃) δ 8.71 (s,1H), 8.64 (d, J=3.9 Hz, 1H), 8.41 (m, 1H), 8.03 (s, 1H), 7.75-7.54 (m,4H), 7.36 (dd, J=8.1, 5.1 Hz, 1H), 6.81 (t, J=6.0 Hz, 1H), 6.34 (s, 1H),4.74 (d, J=6.0 Hz, 2H), 3.25 (s, 3H).

Example 297

To a solution of the N-Boc-protected compound prepared in Example 294(56 mg, 0.11 mmol) in CH₂Cl₂ (4 mL) at 0° C. was added m-CPBA (42 mg,0.24 mmol). After stirring for 2 hr at room temperature more m-CPBA (13mg, 0.075 mmol) was added. The mixture was stirred at room temperatureovernight, diluted with CH₂Cl₂ (20 mL), and washed with saturated NaHCO₃(20 mL). The organic phase was dried over MgSO₄ and concentrated underreduced pressure. The residue was purified by preparative thin-layerchromatography using a 2.5% MeOH in EtOAc solution as eluent. A solutionof the obtained N-Boc-protected product (29 mg, 49% yield, LCMS:MH⁺=558) and TFA (1 mL) in CH₂Cl₂ (2 mL) was stirred at room temperaturefor 2 hr. The volatiles were removed under reduced pressure. The residuewas dissolved in CH₂Cl₂, neutralized with saturated NaHCO₃, andextracted with CH₂Cl₂. The organic phase was dried over MgSO₄ andconcentrated under reduced pressure. The crude product was purified bypreparative thin-layer chromatography using a 2.5% MeOH in EtOAcsolution as eluent (21 mg, 90% yield). LCMS: MH⁺=458; ¹H NMR (CDCl₃) δ8.64 (s, 2H), 8.20 (m, 1H), 8.01 (s, 1H), 7.73-7.60 (m, 3H), 7.46 (m,1H), 7.35 (s, 1H), 6.82 (t, J=5.9 Hz, 1H), 6.17 (s, 1H), 4.65 (d, J=5.7Hz, 2H), 3.60 (s, 3H).

Example 298

By essentially the same procedure set forth in Preparative Example 127only substituting the compound prepared in Preparative Example 189, theabove compound was prepared. MS: MH⁺=334; mp=170-173° C.

Examples 299-300

By essentially the same procedure set forth in Example 298 onlysubstituting the compound shown in Table 27, Column 2, the compoundsshown in Table 27, Column 3 were prepared: TABLE 27 Ex. Column 2 Column3 CMPD 299

MS: MH⁺ = 348 m.p. = 73-83° C. 300

MS: MH⁺ = 362 m.p. = 165-175° C.

Example 301

To a solution of the compound prepared in Preparative Example 186 (0.1g, 0.21 mmol) in THF (4.0 mL) at −78° C. was added nBuLi (0.57 mL, 2.16Min hexanes, 5.0 eq.) at −78° C. The reaction mixture was stirred 2 hoursat −78° C., quenched with H₂O, warmed to room temperature, and extractedwith EtOAc. The combined organics were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude product was purified byPreparative TLC using a 2.5% (10% NH₄OH in CH₃OH) solution in CH₂Cl₂ aseluent (0.013 g, 20% yield). MS: MH⁺=326; mp=71-72° C.

Example 302

By essentially the same procedure set forth in Example 301 onlysubstituting the compound from Preparative Example 187, the abovecompound was prepared (0.049 g, 68% yield). MS: MH⁺=344; mp=69-71° C.

Example 303

To a solution of 3-H adduct from Preparative Example 187.1 (0.70 g, 2.32mmol) in DMF (4.2 mL) at 0° C. was added POCl₃ (0.67 mL, 7.2 mmol)dropwise. The mixture was stirred for 14 h at rt, cooled to 0° C., andwas quenched by addition of ice. 1N NaOH was carefully added to adjustpH to 8 and the mixture was extracted with CH₂Cl₂ (3×25 mL). The organiclayers were combined, dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The crude product was recrystallized from EtOAc toafford 0.43 g (56%) of a yellow solid. mp 181-183° C.; M+H=330.

Example 304

Step A:

To a solution of aldehyde (100 mg, 0.30 mmol) from Example 303 in THF (1mL) at 0° C. was added cyclohexyl magnesium bromide (0.46 mL, 2.0M inEt₂O) dropwise over 5 min. The resulting mixture was stirred at 0° C.for 2 h and at rt for 12 h. The mixture was cooled to 0° C. and wastreated with sat. aq. NH₄Cl (3 mL) and CH₂Cl₂ (5 mL). The layers wereseparated and the aqueous layer was extracted with CH₂Cl₂ (2×5 mL). Theorganic layers were combined, washed with brine (1×5 mL), dried(Na₂SO₄), filtered and concentrated under reduced pressure to afford 110mg (89%) of a light yellow semisolid. M+H=414. This material was carriedon crude to Step B without further purification.

Step B:

To a solution of alcohol (53 mg, 0.13 mmol) in CH₂Cl₂ (0.5 mL) at 0° C.was added Et₃SiH (24 μL, 0.15 mmol) followed by TFA (24 μL, 0.30 mmol).The mixture was stirred for 2 h at 0° C. and rt for 2 h whereuponadditional portions of Et₃SiH (24 μL, 0.15 mmol) and TFA (24 μL, 0.30mmol) were added and the mixture was stirred for 3 h at rt (untilcomplete by TLC). The mixture was concentrated under reduced pressureand the crude residue was partitioned between CH₂Cl₂ (5 mL) and sat. aq.NaHCO₃ (2.5 mL). The layers were separated and the aqueous layer wasextracted with CH₂Cl₂ (2×5 mL). The organic layers were combined, washedwith brine (1×5 mL), dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude product was purified by prep TLC (8×1000 mM)eluting with CH₂Cl₂/MeOH (22:1) to afford 29 mg (56%) of a yellowsemisolid. M+H=398.

Examples 305-312

By essentially the same procedure set forth in Example 304, utilizingthe aldehyde from Example 303 and substituting the Grignard ororganolithium reagents shown in Column 2 of Table 28, the compounds inColumn 3 of Table 28 were prepared: TABLE 28 CMPD 1. mp (° C.) Ex.Column 2 (Organometallic) Column 3 (Final Structure) 2. M + H 305

1. yellow oil 2. M + H = 392 306

1. red oil 2. M + H = 353 307

1. red oil 2. M + H = 398 308

1. yellow oil 2. M + H = 406 309

1. yellow semisolid 2. M + H = 384 310

1. semisolid 2. M + H = 340 311

1. mp = 141-143 2. M + H = 358 312

1. mp = 148-150 2. M + H = 372

Example 313

To solution of aldehyde (81 mg, 0.25 mmol) from Example 303 in benzene(2.5 mL) was added carboethoxymethylene triphenyl phosphorane (0.12 g,0.33 mmol) in one portion. The mixture was heated at reflux for 24 h,cooled to rt, and concentrated under reduced pressure. The mixture wasdiluted CH₂Cl₂ (5 mL), brine (2 mL) was added, and the layers wereseparated. The aqueous layer was extracted with CH₂Cl₂ (2×4 mL). Theorganic layers were combined, dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The crude product was purified by preparativeTLC (8×1000 μM) eluting with CH₂Cl₂/MeOH (20:1) to afford 98 mg (100%)of white solid. mp 151-153° C.; M+H=400.

Example 314

To a mixture of benzyltriphenylphosphonium bromide (0.59 g, 1.37 mmol)in THF (3 mL) was added NaH (55 mg, 1.37 mmol) and the mixture wasstirred for 30 min. The aldehyde (0.15 g, 0.46 mmol) from Example 303was added in a single portion and the mixture was heated at reflux for36 h. The mixture was cooled to rt and was concentrated under reducedpressure. The mixture was diluted CH₂Cl₂ (5 mL), brine (2 mL) was added,and the layers were separated. The aqueous layer was extracted withCH₂Cl₂ (2×4 mL). The organic layers were combined, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The crude product waspurified by preparative TLC (8×1000 μM) eluting with CH₂Cl₂/MeOH (20:1)to afford 58 mg (32%) of yellow solid. mp 138-141° C.; M+H=404.

Example 315

To a solution of aldehyde (0.20 g, 0.60 mmol) from Example 303 in THF (3mL) was added Ti (i-OPr)₄ (0.36 mL, 1.21 mmol) dropwise followed byaddition of (S)-(−)-2-methyl-2-propanesulfinamide (74 mg, 0.61 mmol).The resulting mixture was stirred for 18 h at reflux, cooled to rt, andquenched with brine (2 mL). The mixture was filtered thru a pad ofCelite which washed with EtOAc (2×2 mL). The layers were separated andthe aqueous layer was extracted with EtOAc (2×4 mL). The organic layerswere combined, dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The crude product was purified by preparative TLC (8×1000 μM)eluting with CH₂Cl₂/MeOH (20:1) to afford 0.21 g (80%) of yellow solid.mp 108-110° C.; M+H=433.

Example 316

Prepared in the same fashion as Example 315 except substituting(R)-(−)-2-methyl-2-propanesulfinamide to afford 0.25 g (94%) as a yellowsolid. mp 107-109° C.; M+H=433.

Example 317

Step A:

To a solution of sulfinimine (50 mg, 0.12 mmol) from Example 316 inCH₂Cl₂ (2.5 mL) at −40° C. was added MeMgBr (96 mL, 0.29 mmol) dropwise.The mixture was stirred for 5 h at −40° C. and was stirred at rt for 12h. An additional portion of MeMgBr (96 mL, 0.29 mmol) and the mixturewas stirred for 12 h. Sat. aq. NH₄Cl (2 mL) was added and the mixturewas extracted with EtOAc (3×4 mL). The organic layers were combined,dried (Na₂SO₄), filtered, and concentrated under reduced pressure toafford 30 mg (58%) of crude residue. This material was taken onto thenext step without purification.

Step B:

The crude material from Step A (30 mg, 0.067 mmol) in MeOH (2 mL) wasadded conc. HCl (2 mL). The mixture was stirred at rt for 12 h and themixture was concentrated to dryness. The crude material was partitionedbetween CH₂Cl₂ (3 mL) and sat. aq. NaHCO₃ (2 mL) and the layers wereseparated. The aqueous layer was extracted with CH₂Cl₂ (2×3 mL) and theorganic layers were combined. The organic layer was dried (Na₂SO₄),filtered, and concentrated under reduced pressure to afford 6 mg (24%)of the title compound as a light yellow solid. mp 100-102° C.; M+H=345.

Example 318

To a solution of aldehyde (75 mg, 0.23 mmol) from Example 300 inTHF/CH₂Cl₂ (5 mL/1 mL) at rt was added MeONH₂.HCl (38 mg, 0.46 mmol)followed by dropwise addition of pyridine (46 μL, 0.57 mmol). Themixture was stirred for 72 h at rt whereupon the mixture wasconcentrated to dryness. The crude material was partitioned betweenCH₂Cl₂ (3 mL) and sat. aq. NaHCO₃ (2 mL) and the layers were separated.The aqueous layer was extracted with CH₂Cl₂ (2×3 mL) and the organiclayers were combined. The organic layer was dried (Na₂SO₄), filtered,and concentrated under reduced pressure. The crude product was purifiedby preparative TLC (3×1000 μM) eluting with CH₂Cl₂/MeOH (22:1) to afford90 mg (100%) of light yellow solid. mp 173-175° C.; M+H=359.

Example 319

To solution of aldehyde (60 mg, 0.18 mmol) from Example 303 at EtOH (2.5mL) was added oxindole (48 mg, 0.37 mmol) followed by piperidine (3drops). The mixture was heated at reflux for 14 h and the mixture wascooled to rt. The resultant precipitate was filtered and washed withcold EtOH (2×2 mL). The product was dried under high vacuum to afford 81mg (100%) of the title compound as an orange/brown solid. mp 182-185°C.; M+H=445.

Example 320

To a solution of 3-H analog (106 mg, 0.35 mmol) from Preparative Example187.10 in AcOH (2 mL) was added 37% aqueous formaldehyde (1.5 ml; 1.40mmol) followed by piperidine (100 μL; 0.37 mmol). The resulting mixturewas stirred at rt for 24 h and the AcOH was removed under reducedpressure. The mixture was diluted with water (2 mL) and neutralized with2M NaOH until pH=8. The aqueous layer was extracted with CH₂Cl₂ (3×7 mL)and the organic layers were combined. The organic layer washed withbrine (1×4 mL), dried (Na₂SO₄), filtered, and concentrated under reducedpressure to afford 96 mg (69%) of an off-white solid. mp 88-90° C.; M+H399.

Examples 321-322

By essentially the same procedure set forth in Example 320 onlysubstituting the amines in Column 2 of Table 29 and employing the 3-Hadduct from Preparative Example 187.10, the compounds in Column 3 ofTable 29 were prepared: TABLE 29 CMPD 1. mp (° C.) Ex. Column 2 (Amine)Column 3 (Final Structure) 2. M + H 321

1. mp = 178-180 2. M + H = 401 322

1. mp = 102-104 2. M + H = 414

Example 323

To a solution of 3-H analog (113 mg, 0.38 mmol) from Preparative Example187.10 in CH₂Cl₂ (5 mL) at rt was added AlCl₃ (215 mg, 1.61 mmol)followed by AcCl (100 mL, 1.40 mmol). The mixture was heated at refluxfor 12 h and was cooled to rt. The mixture was treated sequentially with3M HCl (3 mL) followed by sat. aq. NaHCO₃ (until pH=8). The layers wereseparated and the aqueous layer was extracted with CH₂Cl₂ (2×5 mL). Theorganic layers were combined, dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The crude product was purified by preparativeTLC (8×1000 mM) eluting with CH₂Cl₂/MeOH (20:1) to afford 68 mg (52%) ofwhite solid. mp 220-221° C.; M+H=344.

Example 324

Utilizing the method described in Example 323, except employing benzoylchloride, the title compound was prepared in 61% yield as a white solid.mp 172-175° C.; M+H=406.

Example 325

To a solution of ketone (100 mg, 0.29 mmol) from Example 323 in CH₂Cl₂(2.5 mL) at 0° C. was added MeMgBr (0.35 mL, 3.0M in Et₂O) dropwise. Theresulting mixture was stirred for 18 h at rt and was carefully quenchedby addition of sat. aq. NH₄Cl (2 mL) and CH₂Cl₂ (2 mL) were added. Thelayers were separated and the aqueous layer was extracted with CH₂Cl₂(2×4 mL). The organic layers were combined, dried (Na₂SO₄), filtered,and concentrated under reduced pressure. The crude product was purifiedby preparative TLC (8×1000 μM) eluting with CH₂Cl₂/MeOH (10:1) to afford68 mg (52%) of a yellow solid. mp 160-162° C.; M+H=360.

Example 326

To a solution of ketone (84 mg, 0.24 mmol) from Example 323 in MeOH/THF(1:1; 2 mL total) at 0° C. was added NaBH₄ (12 mg, 0.30 mmol) in oneportion. The resulting mixture was stirred for 18 h at rt whereupon andadditional portion of NaBH₄ (12 mg, 0.30 mmol) was added. The mixturewas stirred for 12 h whereupon the mixture was quenched with icefollowed by addition of 1M NaOH to adjust the pH=9. The mixture wasdiluted with CH₂Cl₂ (5 mL). The layers were separated and the aqueouslayer was extracted with CH₂Cl₂ (2×4 mL). The organic layers werecombined, dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The crude product was purified by preparative TLC (8×1000 μM)eluting with CH₂Cl₂/MeOH (10:1) to afford 25 mg (30%) of a yellow solid.mp 148-150° C.; M+H=346.

Example 327

Using the same procedure as outlined in Example 326, the ketone (84 mg,0.21 mmol) was converted to 53 mg (62%) as a light yellow solid. mp78-80° C.; M+H=408.

Example 328

To a solution of 3-H adduct (1.3 g, 4.31 mmol) from Preparative Example187.10 in CH₂Cl₂ (50 mL) was added Eschenmoser's salt (0.79 g, 4.31mmol) followed by dropwise addition of TFA (0.56 mL, 7.33 mmol). Themixture was stirred at rt for 48 h and was diluted with CH₂Cl₂ (250 mL).The organic layer washed with sat. aq. NaHCO₃ (2×125 mL) to afford 1.41h (92%) of a yellow solid. mp 231-233° C.; M+H=359.

Example 329

To a solution of tertiary amine adduct (100 mg, 0.28 mmol) from Example328 in 50% aq. DMF (5 mL) in a pressure tube was added KCN (0.15 g, 2.32mmol). The tube was capped and heated at 100° C. for 96 h. The mixturewas cooled to rt and was diluted with EtOAc (25 mL). The organic layerwashed with brine (1×5 mL) and water (1×5 mL). The organic layers wasdried (Na₂SO₄), filtered, and concentrated under reduced pressure. Thecrude product was purified by preparative TLC (4×1000 μM) eluting withEtOAc to afford 21 mg (30%) of brown solid. mp 152-155° C.; M+H=341.

Example 330

To a solution of alcohol (45 mg, 0.14 mmol) from Example 17.10 in CH₂Cl₂(0.7 mL) at 0° C. was added Et₃SiH (26 μL, 0.16 mmol) followed by TFA(25 μL, 0.33 mmol). The mixture was stirred for 2 h at 0° C. and rt for2 h whereupon additional portions of Et₃SiH (26 μL, 0.16 mmol) and TFA(25 μL, 0.33 mmol) were added and the mixture was stirred for 4 h at rt(until complete by TLC). The mixture was concentrated under reducedpressure and the crude residue was partitioned between CH₂Cl₂ (3 mL) andsat. aq. NaHCO₃ (1.5 mL). The layers were separated and the aqueouslayer was extracted with CH₂Cl₂ (2×4 mL). The organic layers werecombined, washed with brine (1×5 mL), dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude product was purified byprep TLC (4×1000 mM) eluting with CH₂Cl₂/MeOH (20:1) to afford 21 mg(48%) of a yellow solid. mp 146-148° C.; M+H=316.

Example 331

To a solution of 3-H adduct (90 mg, 0.30 mmol) from Preparative Example187.10 in conc. H₂SO₄ (2 mL) at 0° C. was added fuming HNO₃ (30 μL, 0.72mmol) dropwise. The resulting mixture was stirred for 1 h at 0° C.whereupon ice (˜1 g) was added to the mixture. The resulting precipitatewas collected and was washed with water (2×2 mL) and CH₂Cl₂ (2×2 mL).The crude product was dried under high vacuum to afford 67 mg (60%) ofthe monosulfate salt as a yellow/orange solid. mp 250° C.; M+H (freebase)=392.

Example 332

Step A:

To a solution of aldehyde (0.10 g, 0.39 mmol) from Preparative Example168 in THF (2.5 mL) at 0° C. was added CF₃TMS (64 mL, 0.43 mmol)followed by CsF (10 mg). The resulting mixture was stirred for 2 h at 0°C. and 2 h at rt. 1M HCl (5 mL) was added and the mixture was dilutedwith CH₂Cl₂ (10 mL). The layers were separated, the aqueous layer wasextracted with CH₂Cl₂ (2×10 mL), and the organic layers were combined.The organic layer washed with brine (1×10 mL), dried (Na₂SO₄), filtered,and concentrated under reduced pressure to afford 127 mg (99%) of ayellow semisolid. M+H=328. The crude product was carried on withoutfurther purification.Step B:

By utilizing the general procedure set forth in Example 1, the 7-Cladduct (127 mg, 0.39 mmol) from Example 332, Step A was reacted with3-(aminomethyl)pyridine (73 μL, 0.43 mmol) to afford 80 mg (51%) of thetitle compound as a light yellow solid. mp 68-72° C.; M+H=400.

Example 333

To a solution of aniline (200 mg, 0.69 mmol) from Preparative Example174 in THF (6 mL) at rt was added aldehyde (114 mg, 0.83 mmol) fromPreparative Example 256 followed by dropwise addition of Ti(i-OPr)₄(0.82 mL, 2.77 mmol). The mixture was stirred at reflux for 4 h and wascooled to rt. NaCNBH₃ (347 mg, 5.53 mmol) was added and the mixture wasstirred for 2 h at rt. The mixture was cooled to 0° C., treated with 1MNaOH (4 mL) and brine (1 mL) and stirred for 30 min. The mixture wasextracted with CH₂Cl₂ (3×10 mL) and the organic layers were combined.The organic layer washed with brine (1×7 mL), dried (Na₂SO₄), filtered,and concentrated under reduced pressure. The crude product was purifiedby preparative thin-layer chromatography (8×1000 υM plates) eluting withCH₂Cl₂/MeOH (25:1) to afford 89 mg (31%) of the title compound as ayellow solid. mp 210-213° C.; M+H=411.

Examples 334-337

By essentially the same procedure set forth in Example 333 only byutilizing the anilines shown in Column 2 of Table 30 and the aldehydesshown in Column 3 of Table 30, the compounds in Column 4 of Table 30were prepared: TABLE 30 CMPD 1. mp (° C.) Ex. Column 2 (Aniline) Column3 (Aldehyde) Column 4 (Final Structure) 2. M + H 334

1. mp = 85-87 2. M + H = 425 335

1. mp = 160-162 2. M + H = 451 336

1. mp = 117-119 2. M + H = 382 337

1. mp = 171-175 2. M + H = 400

Example 338

Step A:

Reaction of aniline (0.20 g, 0.69 mmol) with aldehyde (0.13 g, 0.83mmol) under the reaction conditions described in Example 333 afforded 70mg (23%) of thiomethyl derivative as a yellow solid. M+H=428.

Step B:

To a solution of thiomethyl derivative (60 mg, 0.14 mmol) from Example338, Step A in dioxane (2 mL) was added Boc₂O (61 mg, 0.28 mmol)followed by DMAP (21 mg, 0.17 mmol). The mixture was stirred for 14 h atrt and was concentrated under reduced pressure. The crude product waspurified by preparative thin-layer chromatography (6×1000 μM plates)eluting with hexanes/EtOAc (4:1) to afford 61 mg (83%) of the titlecompound as a yellow solid. M+H=528.

Step C:

To a solution of thiomethyl derivative from Example 338, Step B (41 mg,0.078 mmol) in CH₂Cl₂ (2 mL) was added MCPBA (33 mg, 0.19 mmol) in oneportion. The resulting mixture was stirred for 3 h at rt and the mixturewas diluted with CH₂Cl₂ (5 mL) and sat. aq. NaHCO₃ (2.5 mL). The layerswere separated, the aqueous layer was extracted with CH₂Cl₂ (2×5 mL),and the organic layers were combined. The organic layer was dried(Na₂SO₄), filtered, and concentrated under reduced pressure to afford 40mg (92%) of the sulfone adduct as a light yellow solid. M+H=560.

Step D:

To a flask charged with sulfone from Example 338, Step C (75 mg, 0.13mmol) and a stir bar was added morpholine (2 ml; 22 mmol). The mixturewas heated at reflux for 12 h, cooled to rt, and concentrated to drynessunder high vacuum. The crude product was purified by preparativethin-layer chromatography (6×1000 μM plates) eluting with CH₂Cl₂/MeOH(40:1) to afford 41 mg (68%) of the title compound as a yellow solid. mp209-210° C.; M+H=466.

Example 339

The title compound was prepared according to the procedure outlined inExample 338 except using benzyl amine to afford 12 mg (70%) of a whitesolid. mp 194-196; M+H=487.

Example 340

Step A:

To a solution of 5-chloro adduct (0.15 g, 0.34 mmol) in dioxane/DIPEA(2.5 mL/1.0 mL) at rt was added cyclopentylamine (0.041 μL, 0.41 mmol)dropwise. The resulting solution was stirred at reflux for 16 h, cooledto rt, and concentrated under reduced pressure. The crude material waspurified by preparative thin-layer chromatography (8×1000 μM) elutingwith CH₂Cl₂/MeOH (25:1) to afford 148 mg (89%) of a yellow oil. M+H=489.

Step B: Removal of the t-Butoxycarbonyl Protecting Group with TFA

To a solution of the compound prepared in Example 340, Step A (135 mg,0.28 mmol) in CH₂Cl₂ (2 mL) at rt was added TFA (0.54 mL, 7.0 mmol)dropwise. The resulting solution was stirred for 18 h at rt and wasconcentrated under reduced pressure. The crude material was redissolvedin CH₂Cl₂ (5 mL) and the organic layer was sequentially washed with sat.aq. NaHCO₃ (2×2 mL) and brine (1×2 mL). The organic layer was dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The crudematerial was purified by preparative thin-layer chromatography (8×1000μM) eluting with CH₂Cl₂/MeOH (20:1) to afford 105 mg (97%) of whitesolid. mp 120-122° C.; M+H=389.

Example 341

Step A:

By essentially the same procedure set forth in Example 340 onlysubstituting the appropriate amine, the above compound was prepared. MS:MH⁺=431.Step B: Removal to t-Butoxycarbonyl Protecting Group with KOH.

To a mixture of the compound prepared in Example 341, Step A (0.14 g,0.26 mmol) in EtOH:H₂O (3 mL, 2:1) was added KOH (0.29 g, 20 eq.) in oneportion. The resulting solution was stirred at reflux 14 hours, cooledto room temperature, and concentrated under reduced pressure. Theresidue was taken up in CH₂Cl₂ (5 mL) and diluted with saturated NaHCO₃(2 mL). The layers were separated and the aqueous layer extracted withCH₂Cl₂ (2×4 mL). The combined organics were washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thecrude product was purified by preparative TLC (8×1000 μM) eluting with5% MeOH in CH₂Cl₂ solution (0.066 g, 59% yield). MS: MH⁺=432;mp=219-221° C.

Examples 342-397

By essentially the same procedure set forth in Example 340 onlysubstituting the chlorides in Column 2 of Table 31 and removing thet-butoxycarbonyl protecting group by the method shown in Column 3 ofTable 31, the compounds shown in Column 4 of Table 31 were prepared.TABLE 31 Ex. Column 2 Column 3 Column 4 CMPD 342

HCl

MS: MH⁺ = 403 m.p. 151-157° C. 343

HCl

MS: MH⁺ = 466 m.p. 212-217° C. 344

HCl

MS: MH⁺ = 405 m.p. 53-58° C. 345

HCl

MS: MH⁺ = 405 m.p. 63-69° C. 346

HCl

MS: MH⁺ = 363 m.p. 170-171° C. 347

HCl

MS: MH⁺ = 407 m.p. 148-151° C. 348

HCl

MS: MH⁺ = 435 m.p. 56-59° C. 349

HCl

MS: MH⁺ = 445 m.p. 66-68° C. 350

KOH

MS: MH⁺ = 417 m.p. 149-151° C. 351

KOH

MS: MH⁺ = 431 m.p. 111-114° C. 352

KOH

MS: MH⁺ = 417 m.p. 53-58° C. 353

KOH

MS: MH⁺ = 456 m.p. 186-189° C. 354

KOH

MS: MH⁺ = 416 m.p. 210-213° C. 355

TFA

1. mp = 68-70 2. M + H = 494 356

KOH

1. mp = 181-183 2. M + H = 404 357

TFA

1. mp = 69-71 2. M + H = 494 358

KOH

1. mp = 182-184 2. M + H = 404 359

KOH

1. mp = 202-204 2. M + H = 418 360

TFA

1. mp = 160-162 2. M + H = 402 361

TFA

1. mp = 151-153 2. M + H = 416 362

KOH

1. mp = 140-143 2. M + H = 418 363

KOH

1. mp = 139-142 2. M + H = 418 364

KOH

1. mp = 115-117 2. M + H = 418 366

TFA

1. mp = 102-104 2. M + H = 445 367

TFA

1. mp = 118-120 2. M + H = 474 368

TFA

1. mp = 106-108 2. M + H = 474 369

TFA

1. mp = 160-161 2. M + H = 464 370

TFA

1. mp = 93-95 2. M + H = 432 371

KOH

1. mp = 108-110 2. M + H = 432 372

KOH

1. mp = 180-182 2. M + H = 418 373

TFA

1. mp = 169-170 2. M + H = 417 374

TFA

1. mp = 77-79 2. M + H = 479 375

TFA

1. mp = 76-79 2. M + H = 479 376

TFA

1. mp = 105-107 2. M + H = 389 377

TFA

1. mp = 105-107 2. M + H = 389 378

TFA

1. mp = 130-133 2. M + H = 389 379

TFA

1. mp = 132-135 2. M + H = 431 380

TFA

1. mp = 135-137 2. M + H = 372 381

KOH

1. mp = 78-82 2. M + H = 432 382

TFA

1. mp = 101-103 2. M + H = 432 383

TFA

1. mp = 92-95 2. M + H = 472 384

TFA

1. mp = 107-111 2. M + H = 444 384.10

TFA

1. mp =2. M + H = 417 384.11

TFA

1. mp = 210-212 2. M + H = 391 385

TFA

1. mp = 122-124 2. M + H = 403 386

TFA

1. mp = 186-188 2. M + H = 491 387

TFA

1. mp = 173-175 2. M + H = 483 388

TFA

1. mp = 167-169 2. M + H = 450 389

TFA

1. mp = 90-92 2. M + H = 374 390

TFA

1. mp = 113-115 2. M + H = 404 391

TFA

1. mp = 114-116 2. M + H = 404 392 HNMe₂ TFA

LCMS: MH⁺ = 347; 393 H₂NMe TFA

LCMS: MH⁺ = 333; 394

TFA

LCMS: MH⁺ = 359; 395

TFA

LCMS: MH⁺ = 405; 396

TFA

LCMS: MH⁺ = 405; 397

TFA

LCMS: MH⁺ = 391;Additional data for select example shown below:

Example 392

¹H NMR (DMSO-d₆) δ 8.65 (s, 1H), 8.46 (d, J=3.3 Hz, 1H), 8.21 (t, J=6.6Hz, 1H), 7.90 (s, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.35 (dd, J=7.8, 4.8 Hz,1H), 5.46 (s, 1H), 4.61 (d, J=6.9 Hz, 2H), 3.01 (s, 6H).

Example 393

¹H NMR (CDCl₃) δ 8.65 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 7.76 (s, 1H),7.70 (m, 1H), 7.32 (dd, J=8.1, 4.8 Hz, 1H), 6.43 (t, J=6.0 Hz, 1H), 5.08(s, 1H), 4.80 (m, 1H), 4.56 (d, J=6.0 Hz, 2H), 2.96 (d, J=5.1 Hz, 3H).

Example 394

¹H NMR (CDCl₃) δ 8.68 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 7.76 (s, 1H),7.72 (m, 1H), 7.32 (dd, J=7.8, 5.4 Hz, 1H), 6.55 (t, J=5.7 Hz, 1H), 5.53(s, 1H), 5.35 (s, 1H), 4.62 (d, J=5.7 Hz, 2H), 2.49 (m, 1H), 0.75 (m,2H), 0.51 (m, 2H).

Example 395

¹H NMR (CDCl₃) δ 8.65 (s, 1H), 8.60 (d, J=4.0 Hz, 1H), 7.75 (s, 1H),7.69 (m, 1H), 7.33 (dd, J=8.1, 5.1 Hz, 1H), 6.45 (t, J=6.0 Hz, 1H), 5.07(s, 1H), 4.69 (m, 1H), 4.54 (d, J=6.0 Hz, 2H), 3.98 (m, 1H), 3.79 (dd,J=10.8, 2.4 Hz, 1H), 3.59 (dd, J=11.1, 7.2 Hz, 1H), 1.59-1.36 (m, 4H),0.94 (t, J=6.9 Hz, 3H).

Example 396

¹H NMR (CDCl₃) δ 8.60 (s, 1H), 8.56 (d, J=4.2 Hz, 1H), 7.73 (s, 1H),7.66 (m, 1H), 7.31 (dd, J=7.8, 4.8 Hz, 1H), 6.51 (t, J=6.0 Hz, 1H), 5.05(s, 1H), 4.86 (d, J=6.6 Hz, 1H), 4.50 (d, J=6.0 Hz, 2H), 3.94 (m, 1H),3.78 (dd, J=11.1, 2.4 Hz, 1H), 3.57 (dd, J=11.1, 7.2 Hz, 1H), 1.57-1.34(m, 4H), 0.91 (t, J=7.2 Hz, 3H).

Example 397

¹H NMR (CDCl₃) δ 8.65 (s, 1H), 8.59 (d, J=4.5 Hz, 1H), 7.75 (s, 1H),7.69 (m, 1H), 7.31 (m, 1H), 6.43 (t, J=6.0 Hz, 1H), 5.06 (s, 1H), 4.88(m, 1H), 4.55 (d, J=6.0 Hz, 2H), 3.70 (m, 2H), 3.38 (m, 2H), 1.79-1.61(m, 4H).

Examples 398-416

By essentially the same conditions set forth in Example 341, Steps A andB only substituting the compound prepared in Preparative Example 193.10,the compounds in Column 4 of Table 32 were prepared. TABLE 32 Ex. Column2 Column 3 Column 4 CMPD 398

MS: MH⁺ = 419 m.p. 102-105° C. 399

MS: MH⁺ = 421 m.p. 79-81° C. 400

MS: MH⁺ = 421 m.p. 78-79° C. 401

MS: MH⁺ = 433 m.p. 228-231° C. 402

MS: MH⁺ = 447 m.p. 97-102° C. 403

MS: MH⁺ = 421 m.p. ° C. 404

MS: MH⁺ = 421 m.p. ° C. 405

MS: MH⁺ = 386 m.p. ° C. 407

KOH

1. mp = 98-100 2. M + H = 390 408

TFA

1. mp = 170-173 2. M + H = 404 409

KOH

1. mp = 219-221 2. M + H = 420 410

KOH

1. mp = 110-112 2. M + H = 448 411

TFA

1. mp = 81-83 2. M + H = 448 412

TFA

1. mp = 136-138 2. M + H = 448 413 NaOMe KOH

1. mp = 107-110 2. M + H = 351 414

LCMS: MH⁺ = 375;Additional data for select examples shown below:

Example 414

¹H NMR (DMSO-d₆) δ8.26 (s, 1H), 8.23 (m, 1H), 8.13 (m, 1H), 7.90 (s,1H), 7.40-7.27 (m, 3H), 5.34 (s, 1H), 4.49 (d, J=6.3 Hz, 2H), 2.56 (m,1H), 0.67 (m, 2H), 0.35 (m, 2H).

Example 403

¹H NMR (DMSO-d₆+CDCl₃) δ 8.08 (s, 1H), 7.90 (d, J=6.3 Hz, 1H), 7.49 (s,1H), 7.34 (t, J=6.3 Hz, 1H), 7.16-7.09 (m, 2H), 5.65 (d, J=6.6 Hz, 1H),4.97 (s, 1H), 4.90 (s, 1H), 4.29 (d, J=6.3 Hz, 2H), 3.70 (m, 1H), 3.46(m, 1H), 3.34 (m, 1H), 1.35-1.17 (m, 4H), 0.71 (t, J=7.2 Hz, 3H).

Example 404

¹H NMR (DMSO-d₆) δ8.21 (s, 1H), 8.12 (d, J=6.6 Hz, 1H), 8.06 (m, 1H),7.86 (s, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 6.73 (d,J=8.7 Hz, 1H), 5.28 (s, 1H), 4.70 (t, J=5.1 Hz, 1H), 4.41 (d, J=6.6 Hz,2H), 4.00 (s, 1H), 3.39 (m, 1H), 1.53 (m, 1H), 1.36-1.25 (m, 3H), 0.86(t, J=7.0 Hz, 3H).

Examples 417-421

By the procedure set forth in Chem. Pharm. Bull. 1999, 47, 928-938.utilizing the oxygen or sulfur nucleophiles shown in Column 2 asdescribed of Table 33 and by employing the cleavage method listed inColumn 3 of Table 33, the compounds in Column 4 of Table 33 wereprepared: TABLE 33 CMPD 1. mp. Ex. Column 2 (Nucleophile) Column 3(Cleavage method) Column 4 (Final Structure) 2. M + H 417 NaSMe TFA

1. mp = 172-175 2. M + H = 351 418 NaSt-Bu TFA

1. mp = 165-168 2. M + H = 392 419 NaSPh TFA

1. mp = 154-156 2. M + H = 412 420 NaOMe TFA

1. mp = 161-163 2. M + H = 335 421 NaOPh TFA

1. mp = 64-66 2. M + H = 397

Example 422

To a solution of amino compound (18 mg, 0.043 mmol) from Example 373 inCH₂Cl₂ (1 mL) at rt was added DIPEA (10 μL, 0.056 mmol) followed byMeSO₂Cl (4 mL, 0.052 mmol). The mixture was stirred at rt for 12 h andwas diluted with CH₂Cl₂ (2 mL) and sat. aq. NaHCO₃ (2 mL). The layerswere separated and the organic layer was extracted with brine (1×2 mL).The organic layer was dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The crude material was purified by preparativethin-layer chromatography (4×1000 μM) eluting with CH₂Cl₂/MeOH (20:1) toafford 16 mg (75%) of white solid. mp 152-154° C.; M+H=495.

Examples 423-424

Utilizing the procedure outlined in Example 422, the amino compounds(Column 2) were converted to the corresponding methylsulfonamides(Column 3) in Table 34. TABLE 34 CMPD 1. mp. Ex. Column 2 (Amine) Column3 (Final Structure) 2. M + H 423

1. mp = 166-168 2. M + H = 467 424

1. mp = 165-168 2. M + H = 467

Example 425

Step A:

A mixture of the compound prepared in Preparative Example 194 (132 mg,0.25 mmol), tributylvinyltin (95 mg, 0.30 mmol) andtetrakis(triphenylphospine)palladium (29 mg, 0.025 mmol) in anhydrousdioxane (5 mL) was refluxed under N₂ for 24 hr. The solvent wasevaporated and the residue was purified by flash chromatography using2:1 CH₂Cl₂:EtOAc as eluent to yield yellow waxy solid (53 mg, 50%).LCMS: MH⁺=428.Step B:

A mixture of the compound prepared in Example 425, Step A (50 mg, 0.12mmol) and KOH (100 mg, 1.80 mmol) in ethanol (3 mL) and H₂O (0.6 mL) wasstirred at 70° C. under N₂ for 24 hr. NaHCO₃ (1.0 g), Na₂SO₄ (2.0 g),and CH₂Cl₂ (20 mL) were added, the mixture was shaken and then filtered.The solvent was evaporated and the residue was purified by flashchromatography using 20:1:0.1 CH₂Cl₂:MeOH:conc.NH₄OH as eluent to yieldyellow waxy solid (17 mg, 45%). LCMS: MH⁺=328. Mp=48-51° C.

Example 426

Step A:

By essentially the same procedure set forth in Example 425, Step A onlyusing tributylmethylethynyltin, the compound shown above was prepared.Step B:

A mixture of the compound prepared in Example 426, Step A (150 mg, 0.34mmol) and PtO₂ (30 mg, 0.13 mmol) in glacial acetic acid (5 mL) wasstirred under 1 atmosphere of H₂ for 20 hr. The mixture was filtered,fresh PtO₂ (30 mg, 0.13 mmol) was added and the mixture was stirredunder 1 atmosphere of H₂ for 2.5 hr. The mixture was poured onto Na₂CO₃(20 g) and H₂O (200 mL) and it was extracted with CH₂Cl₂ (4×20 mL). Thecombined extracts were dried over Na₂SO₄ and filtered. The solvent wasevaporated and the residue was purified by flash chromatography using1:1 CH₂Cl₂:EtOAc as eluent to yield yellow waxy solid (68 mg, 45%).Step C:

By essentially the same procedure set forth in Example 425, Step B onlysubstituting the compound prepared in Example 426, Step B, the compoundshown above was prepared, MS: MH⁺=344. Mp=110-112° C.

Example 427

Step A:

A mixture of the compound prepared in Preparative Example 194 (527 mg,1.00 mmol), triethyl(trifluoromethyl)silane (666 mg, 3.60 mmol),potassium fluoride (210 mg, 3.60 mmol), and CuI (850 mg, 4.46 mmol) inanhydrous DMF (4 mL) was stirred in a closed pressure vessel at 80° C.for 72 hr. CH₂Cl₂ (80 mL) was added and the mixture was filtered throughCelite. The solvent was evaporated and the residue was purified by flashchromatography using 2:1 CH₂Cl₂:EtOAc as eluent to yield pale orangewaxy solid (70 mg, 15%). LCMS: M⁺=470.Step B:

TFA (0.70 mL) was added at 0° C. under N₂ to a stirred solution of thecompound prepared in Example 427, Step A (70 mg, 0.15 mmol), inanhydrous CH₂Cl₂ (3 mL). The mixture was stirred at 0° C. for 10 min,then at 25° C. for 2 hr. It was poured into 10% aqueous Na₂CO₃ (50 mL),extracted with CH₂Cl₂ (3×15 mL), dried over Na₂SO₄, and filtered. Thesolvent was evaporated and the residue was purified by flashchromatography using EtOAc as eluent to yield off-white solid (40 mg,73%). LCMS: M⁺=370. Mp=156-158° C.

Example 428

Step A:

A mixture of the compound prepared in Preparative Example 193 (100 mg,0.28 mmol), tetracyclopropylltin (91 mg, 0.32 mmol), Pd₂ dba₃ (8.0 mg,0.009 mmol) and Pd(Pt-Bu₃)₂ (9.0 mg, 0.017 mmol) in anhydrous dioxane (3mL) was refluxed under N₂ for 27 hr. The solvent was evaporated and theresidue was purified by flash chromatography using 1:1 CH₂Cl₂:EtOAc aseluent to yield colorless waxy solid (38 mg, 38%). LCMS: MH⁺=366.Step B:

A mixture of the compound prepared in Example 428, Step A (36 mg, 0.10mmol) and KOH (300 mg, 5.40 mmol) in ethanol (3 mL), 1,2-dimethoxyethane(3.0 mL0 and H₂O (0.8 mL) was refluxed under N₂ for 4 hr. It was pouredinto saturated aqueous NaHCO₃ (100 mL), extracted with CH₂Cl₂ (5×10 mL),dried over Na₂SO₄, and filtered. The solvent was evaporated and theresidue was purified by flash chromatography using 30:1 EtOAc:MeOH aseluent to yield colorless waxy (18 mg, 69%). LCMS: MH⁺=266.Step C:

N-bromosuccinimide (12 mg, 0.068 mmol) in anhydrous CH₃CN (2 mL) wasadded under N₂ to a stirred solution of the compound prepared in Example428, Step B (18 mg, 0.068 mmol), in anhydrous CH₃CN (2 mL). The mixturewas stirred at 25° C. for 2 hr. The solvent was evaporated and theresidue was purified by flash chromatography using EtOAc as eluent toyield 5 mg (17%) of the dibromo compound (white solid, LCMS: MH⁺=370,mp=150-152° C.) and 8 mg (34%) of the monobromo compound (colorlesssolid, LCMS: M⁺=344, mp=196-198° C.).

Example 429

Step A:

1,3-propanesultam (72 mg, 0.60 mmol) in anhydrous DMF (3 mL) was addedunder N₂ to 60% NaH in mineral oil (36 mg, 0.90 mmol). The mixture wasstirred for 20 min, then the compound prepared in Preparative Example196 (200 mg, 0.46 mmol) was added. The mixture was stirred at 100° C.for 30 min, the solvent was evaporated and the residue was purified byflash chromatography using EtOAc as eluent to yield colorless solid (150mg, 63%). LCMS: M⁺=523.Step B:

TFA (1.5 mL) was added at 0° C. under N₂ to a stirred solution of thecompound prepared in Preparative Example 196 (140 mg, 0.27 mmol), inanhydrous CH₂Cl₂ (5 mL). The mixture was stirred at 0° C. for 10 min,then at 25° C. for 2 hr. It was poured onto Na₂CO₃ (10 g), extractedwith CH₂Cl₂ (3×50 mL), and filtered. The solvent was evaporated and theresidue was purified by flash chromatography using 40:1 EtOAc:MeOH aseluent to yield white solid (32 mg, 28%). LCMS: M⁺=423. Mp=218-220° C.

Example 430

3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (1equivalent) (prepared as described in Preparative Example 129), or3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (1 equivalent)(prepared as described in Preparative Example 127), R₁NH₂ (1.2equivalents) and diisopropyl ethylamine (2 equivalents) were dissolvedin anhydrous 1,4-dioxane and the mixture was heated at 75° C. for thetime given in Table 97. The solution was evaporated to dryness and theresidue was chromatographed on a silica gel column as described in Table97, to give the title compound.

Using the appropriate reactants and essentially the same procedure asdescribed above, the products of Examples 431 to 438 were prepared.Variations in the reaction conditions are noted in Table 35. TABLE 35Ex. Structure MW FABMS MH⁺ Reaction Conditions Yield ChromatographicData 431

463.8 463.0 75° C./ 26 h 52% 15 × 2.5 cm 0.5-2% (10% Conc. ammoniumhydroxide in methanol)- dichloromethane 432

429.3 429.2 75° C./ 26 h 25° C./ 39 h 53% 15 × 5 cm Dichloromethane;1.5% (10% Conc. ammonium hydroxide in methanol)- dichloromethane 433

477.8 477.1 75° C./ 26 h 48% 15 × 5 cm Dichloromethane; 3.5-15% (10%Conc. ammonium hydroxide in methanol)- dichloromethane 434

477.8 477.0 75° C./ 26 h 50% 15 × 5 cm Dichloromethane; 3.5-15% (10%Conc. ammonium hydroxide in methanol)- dichloromethane 435

434.8 434.1 75° C./ 24 h 25° C./ 65 h 53% 15 × 2.5 cm 3% (10% Conc.ammonium hydroxide in methanol)- dichloromethane 436

434.8 434.2 75° C./ 27 h 31% 15 × 2.5 cm 3% (10% Conc. ammoniumhydroxide in methanol)- dichloromethane 437

438.7 438.1 75° C./ 21 h 25° C./ 46 h 97% 15 × 2.5 cm 0.25% (10% Conc.ammonium hydroxide in methanol)- dichloromethane 438

438.7 438.1 75° C./ 28 h −20° C./ 72 h 95% 60 × 2.5 cm 20% Ethyl acetatein hexaneAdditional physical data for the compounds are given below:

Example 431

Reactants: 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine(110 mg, 0.318 mmoles) (prepared as described in Preparative Example129); 3-(aminomethyl)piperidine-1-carboxamide (60 mg, 0.382 mmoles)(prepared as described in Preparative Example 241 above); diisopropylethylamine (0.111 mL, 0.636 mmoles); anhydrous 1,4-dioxane (2.5 mL).Physical properties: HRFABMS: m/z 463.0628 (MH⁺). Calcd. forC₁₉H₂₁N₆OBrCl: m/z 463.0649: δ_(H) (CDCl₃) 1.38 (1H, m, CH₂), 1.52 (1H,m, CH₂), 1.73 (1H, m, CH), 1.93 (1H, m, CH₂), 2.02 (1H, m, CH₂), 2.98(1H, m, CH₂), 3.06 (1H, m, CH₂), 3.37 (2H, m, CH₂), 3.58 (1H, m, CH₂),3.82 (1H, m, CH₂), 4.87 (2H, bm, CONH₂), 6.28 (1H, s, H₆), 7.02 (1H, m,NH), 7.36 (2H, m, Ar—H), 7.45 (1H, m, Ar—H), 7.68 (1H, m, Ar—H) and 8.00ppm (1H, s, H₂); δ_(C) (CDCl₃) CH₂: 23.7, 28.1, 44.6, 45.5, 47.2; CH:35.2, 87.4, 127.2, 130.1, 130.3, 131.6, 143.9: C: 83.1, 132.1, 138.6,145.5, 146.5, 158.0, 158.4.

Example 432

Reactants: 3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (500 mg,1.62 mmoles) (prepared as described in Preparative Example 127);3-(aminomethyl)piperidine-1-carboxamide (306 mg, 1.944 mmoles) (preparedas described in Preparative Example 241 above); diisopropyl ethylamine(0.566 mL, 3.24 mmoles); anhydrous 1,4-dioxane (13 mL). Physicalproperties: HRFABMS: m/z 429.1031 (MH⁺). Calcd. for C₁₉H₂₂N₆OBr: m/z429.1038; δ_(H) (CDCl₃) 1.44 (1H, m, CH₂), 1.59 (1H, m, CH₂), 1.79 (1H,m, CH), 2.01 (1H, m, CH₂), 2.08 (1H, m, CH₂), 3.03 (1H, m, CH₂), 3.13(1H, m, CH₂), 3.39 (1H, m, CH₂), 3.47 (1H, m, CH₂), 3.63 (1H, m, CH₂),3.90 (1H, m, CH₂), 4.88 (2H, bm, CONH₂), 6.40 (1H, s, H₆), 6.90 (1H, m,NH), 7.53 (2H, m, Ar—H), 8.02 (1H, s, H₂) and 8.12 (1H, m, Ar—H); δ_(C)(CDCl₃) CH₂: 23.7, 28.2, 44.7, 45.5, 47.3; CH: 35.2, 82.9, 127.5, 127.5,128.7, 128.7, 130.0, 143.9; C: 83.0, 138.5, 145.8, 147.1, 158.3, 158.5.

Example 433

Reactants: 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine(347 mg, 1.01 mmoles) (prepared as described in Preparative Example129); 3-(aminoethyl)piperidine-1-carboxamide (208 mg, 1.21 mmoles)(prepared as described in Preparative Example 242 above); diisopropylethylamine (0.393 mL, 2.02 mmoles); anhydrous 1,4-dioxane (9 mL).Physical properties: δ_(H) (CDCl₃) 1.24 (1H, m, CH₂), 1.55 (1H, m, CH),1.72 (4H, m, CH₂), 1.93 (1H, m, CH₂), 2.69 (1H, m, CH₂), 2.94 (1H, m,CH₂), 3.55 (2H, m, CH₂), 3.73 (1H, m, CH₂), 3.98 (1H, m, CH₂), 4.83 (2H,bm, CONH₂), 6.55 (1H, s, H₆), 6.78 (1H, m, NH), 7.41 (2H, m, Ar—H), 7.50(1H, m, Ar—H), 7.75 (1H, m, Ar—H) and 8.04 ppm (1H, s, H₂); δ_(C)(CDCl₃) CH₂: 24.6, 30.7, 32.6, 39.9, 45.3, 49.3; CH: 33.3, 87.5, 127.4,130.1, 130.2, 131.6, 143.8; C: 83.2, 132.1, 138.8, 145.7, 146.2, 158.1,158.1.

Example 434

Reactants: 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine(275 mg, 0.803 mmoles) (prepared as described in Preparative Example129); 4-(aminoethyl)piperidine-1-carboxamide (165 mg, 0.963 mmoles)(prepared as described in Preparative Example 243 above); diisopropylethylamine (0.311 mL, 0.963 mmoles); anhydrous 1,4-dioxane (7.2 mL).Physical properties: δ_(H) (d₆-DMSO) 1.00 (2H, m, CH₂), 1.50 (1H, m,CH), 1.59 (2H, m, CH₂), 1.67 (2H, m, CH₂), 2.60 (2H, m, CH₂), 3.48 (2H,m, CH₂), 3.70 (2H, m, CH₂), 5.84 (2H, bs, CONH₂), 6.43 (1H, s, H₆), 7.50(2H, m, Ar—H), 7.62 (2H, m, Ar—H), 8.30 (1H, s, H₂) and 8.36 ppm (1H, m,NH); δ_(C) (d₆-DMSO)CH₂: 31.5, 31.5, 34.8, 43.5, 43.5, 43.5; CH: 32.8,86.8, 127.1, 129.7, 130.3, 131.0, 143.3; CH: 81.3, 131.0, 138.7, 145.1,146.4, 157.3, 157.8.

Example 435

Reactants: 3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (174 mg,0.507 mmoles) (prepared as described in Preparative Example 129) and3-(aminomethyl)-1-methylpiperidine (65 mg, 0.507 mmoles) (prepared asdescribed in Preparative Example 244 above); diisopropyl ethylamine(0.178 mL, 1.014 mmoles); anhydrous 1,4-dioxane (2.5 mL). Physicalproperties: HRFABMS: m/z 434.0742 (MH⁺). Calcd. for C₁₉H₂₂N₅BrCl: m/z434.0747; δ_(H) (CDCl₃) 1.18 (1H, m, CH₂), 1.68 (1H, m, CH₂), 1.80 (1H,m, CH₂), 1.87 (1H, m, CH₂), 1.96 (1H, m, CH), 2.14 (2H, m, CH₂), 2.32(3H, s, NCH₃), 2.75 (1H, m, CH₂), 2.29 (1H, m, CH₂), 3.42 (2H, m, —NHCH₂CH), 6.36 (1H, s, H₆), 6.64 (1H, bm, NH), 7.41 (2H, m, Ar—H), 7.51 (1H,m, Ar—H), 7.74 (1H, m, Ar—H) and 8.06 ppm (1H, s, H₂); δ_(C) (CDCl₃)CH₃: 46.6; CH₂: 24.4, 27.9, 46.1, 56.1, 59.6; CH: 36.0, 87.4, 127.1,130.1, 130.2, 131.6, 143.8; C: 83.2, 132.1, 138.9, 145.6, 146.4, 158.2.

Example 436

Reactants: 3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (111.4 mg,0.325 mmoles) (prepared as described in Preparative Example 129);4-(aminomethyl)-1-methylpiperidine (50 mg, 0.39 mmoles) (prepared asdescribed in Preparative Example 245 above); diisopropyl ethylamine(0.1135 mL, 0.65 mmoles); anhydrous 1,4-dioxane (1.5 mL). Physical data:HRFABMS: m/z 434.0735 (MH⁺). Calcd. for C₁₉H₂₂N₅BrCl: m/z 434.0747;δ_(H) (CDCl₃) 1.42 (2H, m, CH₂), 1.72 (1H, m, CH), 1.82 (2H, m, CH₂),1.93 (2H, m, CH₂), 2.20 (3H, s, NCH₃), 2.89 (2H, m, CH₂), 3.34 (2H, m,—NHCH ₂CH), 6.31 (1H, s, H₆), 6.46 (1H, m, NH), 7.36 (2H, m, Ar—H), 7.46(1H, m, Ar—H), 7.70 (1H, m, Ar—H) and 8.00 ppm (1H, s, H₂); δ_(C)(CDCl₃) CH₃: 46.4; CH₂: 30.2, 30.2, 48.0, 55.3, 55.3; CH: 35.4, 87.5,127.2, 130.2, 130.2, 131.6, 143.8; C: 83.3, 132.2, 138.9, 145.7, 146.4,158.1.

Example 437

Reactants: 3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (191 mg,0.557 mmoles) (prepared as described in Preparative Example 129);3-(aminomethyl)benzonitrile (88.3 mg, 0.668 mmoles) (prepared asdescribed in Preparative Example 246 above); diisopropyl ethylamine(0.192 mL, 1.114 mmoles); anhydrous 1,4-dioxane (4.5 mL). Physical data:HRFABMS: m/z 438.0125 (MH⁺). Calcd. for C₁₉H₁₂N₅BrCl: m/z 438.0121;δ_(H) (CDCl₃) 4.76 (2H, d, —CH ₂NH—), 6.32 (1H, s, H₆), 7.00 (1H, m,—CH₂NH—), 7.40 (2H, m, Ar—H), 7.46 (1H, m, Ar—H), 7.55 (1H, m, Ar—H),7.67 (2H, m, Ar—H), 7.71 (1H, m, Ar—H), 7.75 (1H, m Ar—H) and 8.10 ppm(1H, s, H₂); δ_(C) (CDCl₃) CH₂: 45.5; CH: 88.2, 127.2, 130.0, 130.2,130.4, 130.6, 131.4, 131.6, 131.9, 144.1; C: 83.8, 113.4, 118.3, 132.0,137.8, 138.3, 145.6, 145.9, 158.0.

Example 438

Reactants: 3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (233.5 mg,0.681 mmoles) (prepared as described in Preparative Example 129);4-(aminomethyl)benzonitrile (108 mg, 0.817 mmoles) (prepared asdescribed in Preparative Example 247 above); diisopropyl ethylamine(0.235 mL, 1.362 mmoles); anhydrous 1,4-dioxane (5.3 mL). Physical data:HRFABMS: m/z 438.0117 (MH⁺) Calcd. for C₂₀H₁₄N₅BrCl: m/z 438.0121; δ_(H)(CDCl₃) 4.80 (2H, d, CH₂), 6.30 (1H, s, H₆), 7.01 (1H, m, NH), 7.40 (2H,m, Ar—H), 7.47 (1H, m, Ar—H), 7.70 (2H, m, Ar—H), 7.72 (2H, m, Ar—H),7.80 (1H, m, Ar—H) and 8.10 ppm (1H, s, H₂); δ_(C) (CDCl₃) CH₂: 45.8;CH: 88.2, 127.2, 127.7, 127.7, 130.2, 130.4, 131.6, 132.9, 132.9, 144.1;C: 83.8, 112.2, 118.4, 132.0, 138.2, 141.5, 145.5, 146.0, 158.0.

Example 439

3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (50 mg,0.146 mmoles) (prepared as described in Preparative Example 129) wasdissolved in anhydrous 1,4-dioxane (5 mL) in a GeneVac Technologiescarousel reaction tube. PS-diisopropyl ethylamine resin (161 mg, 0.5828mmoles) was added to each tube. A freshly prepared 1M solution of theappropriate amine R₁NH₂ in anhydrous 1,4-dioxane (0.2185 mL, 0.2185mmoles) was added to each tube and the tubes were sealed and heated at70° C. for 78 h with magnetic stirring in the reaction block. Each tubewas filtered and the resin washed with anhydrous 1,4-dioxane and thendichloromethane. The combined individual filtrates from each tube wereevaporated to dryness and the residues were each re-dissolved inanhydrous 1,4-dioxane (5 mL) and placed in GeneVac reaction tubes. Toeach tube was added PS-isocyanate resin (594 mg, 0.8742 mmoles) andPS-trisamine resin (129 mg, 0.4371 mmoles) and the tubes were stirred at25° C. for 20 h in the reaction block. The resins were filtered off andwashed with anhydrous 1,4-dioxane and dichloromethane. The filtratesfrom each tube were evaporated to dryness and the residues were eachchromatographed on a silica gel column using the column size and theeluant shown in Table 36, to give the title compounds. TABLE 36 Ex.Structure MW FABMS MH⁺ Yield Chromatographic Data 440

428.7 428.0 81% 15 × 2.5 cm Dichloromethane; 0.5% Methanol indichloromethane 441

428.7 428.0 48% 20 × 2 cm Dichloromethane; 1.5% Methanol indichloromethane 442

428.7 428.0 24% 15 × 2.5 cm Dichloromethane; 1.5% Methanol indichloromethane 443

463.8 463.0 44% 15 × 2.2 cm Dichloromethane; 5% Methanol indichloromethane 444

434.8 434.1 63% 15 × 2.5 cm 5% Methanol in dichloromethane 445

448.8 448.2 65% 15 × 2.5 cm 5% Methanol in dichloromethane 446

448.8 448.1 40% 15 × 2.5 cm Dichloromethane; 0.5% Methanol indichloromethane 447

436.7 436.1 72% 15 × 2.5 cm 0.5% Methanol in dichloromethane 448

450.8 450.0 53% 20 × 2 cm Dichloromethane; 0.5% Methanol indichloromethane 449

381.7 381.0 44% 20 × 2 cm 1.5% Methanol in dichloromethaneAdditional physical data for the compounds are given below:

Example 440

Physical properties: HRFABMS: m/z 428.0272 (MH⁺). Calcd. forC₁₉H₁₆N₅BrCl: m/z 428.0278; δ_(H) (CDCl₃) 3.28 (2H, dd, C₅H₄NCH₂CH₂NH—), 3.94 (2H, ddd, C₅H₄NCH₂CH ₂NH—), 6.40 (1H, s, H₆), 7.22-7.29(3H, m, Ar—H), 7.38-7.44 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.68 (1H,ddd, Ar—H), 7.73 (1H, Ar—H), 8.18 (1H, s, H₂) and 8.68 ppm (1H, NH);δ_(C) (CDCl₃) CH₂: 36.4, 41.5; CH: 87.3, 122.1, 123.6, 127.1, 130.1,130.1, 131.6, 137.0, 143.8, 149.5; C: 83.1, 132.1, 138.9, 145.7, 146.3,158.0, 158.1.

Example 441

Physical properties: HRFABMS: m/z 428.0272 (MH⁺). Calcd. forC₁₉H₁₆N₅BrCl: m/z 428.0278; δ_(H) (CDCl₃) 3.12 (2H, dd, C₅H₄NCH₂CH₂NH—), 3.77 (2H, ddd, C₅H₄NCH₂CH ₂NH—), 6.40 (1H, s, H₆), 6.59 (1H,m, Ar—H), 7.34 (1H, bm, Ar—H), 7.39-7.45 (2H, m, Ar—H), 7.52 (1H, m,Ar—H), 7.62 (1H, m, Ar—H), 7.75 (1H, m, Ar—H), 8.05 (1H, s, H₂) and 8.63ppm (1H, m, NH); δ_(C) (CDCl₃) CH₂: 32.7, 43.1; CH: 87.5, 127.2, 130.2,130.3, 131.6, 136.4, 142.9, 148.3, 149.8; C: 83.5, 132.0, 138.6, 145.6,145.9, 158.1.

Example 442

Physical properties: HRFABMS: m/z 428.0275 (MH⁺). Calcd. forC₁₉H₁₆N₅BrCl: m/z 428.0278; δ_(H) (CDCl₃) 3.13 (2H, dd, C₅H₄NCH₂CH₂NH—), 3.80 (2H, ddd, C₅H₄NCH₂CH ₂NH—), 6.42 (1H, s, H₆), 6.53 (1H,m, Ar—H), 7.23 (2H, m, Ar—H), 7.40-7.46 (2H, m, Ar—H), 7.62 (1H, m,Ar—H), 7.76 (1H, m, Ar—H), 8.07 (1H, s, H₂) and 8.63 ppm (1H, m, NH);δ_(C) (CDCl₃) CH₂: 34.7, 42.5; CH: 87.4, 124.5, 124.5, 127.2, 130.2,130.3, 131.6, 144.0, 150.2, 150.2; C: 83.5, 132.0, 138.6, 145.6, 145.9,146.6, 158.1.

Example 443

Physical properties: HRFABMS: m/z 463.1003 (MH⁺). Calcd. forC₂₀H₂₅N₆BrCl: m/z 463.1013; δ_(H) (CDCl₃) 1.98 (2H, m, ═NCH₂CH ₂CH₂NH—),2.43 (3H, s, NCH₃), 2.67 (2H, m, ═NCH ₂CH₂CH₂NH—), 2.70 (8H, piperazineCH₂), 3.58 (2H, m, ═NCH₂CH₂CH ₂NH—), 6.32 (1H, s, H₆), 7.37-7.43 (2H, m,Ar—H), 7.50 (1H, m, Ar—H), 7.73 (1H, m, Ar—H), 8.06 (1H, s, H₂) and 8.60ppm (1H, m, NH); δ_(C) (CDCl₃) CH₃: 46.1; CH₂: 24.1, 42.8, 53.3, 54.6,54.6, 57.5, 57.5; CH: 87.1, 127.0, 130.0, 130.1, 131.5, 143.4; C: 82.7,132.1, 139.2, 145.7, 146.7, 158.0.

Example 444

Physical properties: HRFABMS: m/z 434.0742 (MH⁺). Calcd. forC₁₉H₂₂N₅BrCl: m/z 434.0747; δ_(H) (CDCl₃) 1.72 (1H, m, CH/CH₂),1.78-1.90 (2H, m, CH/CH₂), 2.02 (3H, m, CH/CH₂), 2.50 (1H, m, CH/CH₂),2.45 (3H, s, NCH₃), 2.51 (1H, m, CH/CH₂), 3.23 (1H, m, CH/CH₂), 3.54(1H, m, CH/CH₂), 3.60 (1H, m, CH/CH₂), 6.32 (1H, s, H₆), 7.38-7.44 (2H,m, Ar—H), 7.51 (1H, m, Ar—H), 7.75 (1H, m, Ar—H), 7.96 (1H, bm, NH) and8.05 ppm (1H, s, H₂); δ_(C) (CDCl₃) CH₃: 40.7; CH₂: 22.7, 29.3, 30.1,39.4, 57.0; CH: 64.2, 87.1, 127.1, 130.0, 130.1, 131.6, 143.8; C: 82.8,132.1, 139.1, 145.7, 146.4, 158.0.

Example 445

Physical properties: HRFABMS: m/z 448.0910 (MH⁺). Calcd. forC₂₀H₂₄N₅BrCl: m/z 448.0904; δ_(H) (CDCl₃) 1.90 (4H, m, CH₂), 2.00 (4H,m, CH₂), 2.84 (2H, m, CH₂), 2.95 (4H, m, CH₂), 3.51 (2H, m, CH₂), 6.32(1H, s, H₆), 7.05 (1H, bm, NH), 7.37-7.43 (2H, m, Ar—H), 7.50 (1H, m,Ar—H), 7.73 (1H, m, Ar—H) and 8.04 ppm (1H, s, H₂); δ_(C) (CDCl₃) CH₂:23.4, 23.4, 24.8, 26.4, 41.8, 53.9, 53.9, 55.2; CH: 87.3, 127.1, 130.1,130.2, 131.6, 143.7; C: 83.0, 132.0, 138.9, 145.7, 146.3, 158.1.

Example 446

Physical properties: HRFABMS: m/z 448.0548 (MH⁺). Calcd. forC₁₉H₂₀N₅OBrCl: m/z 448.0540; δ_(H) (CDCl₃) 1.94 (2H, m, CH₂), 2.09 (2H,m, CH₂), 2.49 (2H, m, CH₂), 3.45 (2H, m, CH₂), 3.51 (4H, m, CH₂), 6.32(1H, s, H₆), 7.37-7.44 (3H, m, Ar—H/NH), 7.51 (1H, m, Ar—H), 7.75 (1H,m, Ar—H) and 8.10 ppm (1H, s, H₂); δ_(C) (CDCl₃) CH₂: 18.0, 26.3, 30.8,39.2, 39.9, 47.5; CH: 87.0, 127.1, 130.1, 130.1, 131.6, 144.1; C: 82.9,132.1, 138.9, 145.6, 146.2, 157.9, 176.2.

Example 447

Physical properties: HRFABMS: m/z 436.0532 (MH⁺). Calcd. forC₁₈H₂₀N₅OBrCl: m/z 436.0540; δ_(H) (CDCl₃) 2.60 (4H, bm, —N(CH ₂CH₂)₂O),2.83 (2H, m, ═NCH ₂CH₂NH—), 3.57 (2H, m, ═NCH₂CH ₂NH—), 3.83 (4H, m,—N(CH₂CH ₂)₂O), 6.37 (1H, s, H₆), 6.99 (1H, bm, NH), 7.38-7.45 (2H, m,Ar—H), 7.51 (1H, m, Ar—H), 7.75 (1H, m, Ar—H) and 8.09 ppm (1H, s, H₂);δ_(C) (CDCl₃) CH₂: 38.2, 53.3, 53.3, 56.2, 66.9, 66.9; CH: 87.6, 127.1,130.1, 130.2, 131.6, 143.9; C; 83.1, 132.1, 138.9, 145.7, 146.2, 158.1.

Example 448

Physical properties: HRFABMS: m/z 450.0688 (MH⁺). Calcd. forC₁₉H₂₂N₅OBrCl: m/z 450.0696; δ_(H) (CDCl₃) 1.98 (2H, m, ═NCH₂CH₂CH₂NH—), 2.58 (4H, m, —N(CH ₂CH₂)₂O), 2.67 (2H, m, ═NCH ₂CH₂CH₂NH—),3.59 (2H, m, ═NCH₂CH₂CH ₂NH—), 3.94 (4H, m, —N(CH₂CH ₂)₂O), 6.31 (1H, s,H₆), 7.37-7.44 (2H, Ar—H), 7.51 (1H, m, Ar—H), 7.78 (1H, m, Ar—H), 8.08(1H, s, H₂) and 8.60 ppm (1H, bm, NH); δ_(C) (CDCl₃) CH₂: 23.7, 42.7,52.9, 52.9, 58.0, 66.6, 66.6; CH: 87.0, 127.1, 130.0, 130.1, 131.5,143.6; C: 82.8, 132.1, 139.1, 145.7, 146.7, 158.0.

Example 449

Physical properties: HRFABMS: m/z 381.0114 (MH⁺). Calcd. forC₁₅H₁₅N₄OBrCl: m/z 381.0118; δ_(H) (CDCl₃) 1.39 (3H, d, CHCH ₃), 2.76(1H, bm, —OH), 3.71 (1H, m, ═CHCH ₂OH), 3.81 (1H, m, ═CHCH ₂OH), 3.88(1H, m, ═CHCH₂OH), 6.38 (1H, s, H₆), 7.38 (2H, m, Ar—H), 7.48 (1H, m,Ar—H), 7.68 (1H, m, Ar—H) and 8.02 ppm (1H, s, H₂); δ_(C) (CDCl₃) CH₃:16.9; CH₂: 65.0; CH: 50.0, 88.0, 127.1, 130.1, 130.3, 131.4, 143.8; C:83.0, 132.0, 138.5, 145.6, 146.0, 158.2.

Example 450

3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (50 mg,0.146 mmoles) (prepared as described in Preparative Example 129) wasdissolved in anhydrous 1,4-dioxane (5 mL) in a GeneVac Technologiescarousel reaction tube. PS-diisopropyl ethylamine resin (161 mg, 0.5828mmoles) was added to each tube. A freshly prepared solution of theappropriate amine R₁NH₂ (0.219 mmoles) in anhydrous 1,4-dioxane (0.3 mL)was added to each tube, with the exception of Example 99-5 in which theamine was dissolved in 10% MeOH in 1,4-dioxane (0.3 mL), and the tubeswere sealed and heated at 70° C. for 74 h with magnetic stirring in thereaction block. Each tube was filtered and the resin washed withanhydrous 1,4-dioxane and then dichloromethane. The combined individualfiltrates from each tube were evaporated to dryness and the residueswere each re-dissolved in anhydrous 1,4-dioxane (5 mL) and placed inGeneVac reaction tubes. To each tube was added PS-isocyanate resin (594mg, 0.8742 mmoles) and PS-trisamine resin (129 mg, 0.4371 mmoles) andthe tubes were stirred at 25° C. for 20 h in the reaction block. Theresins were filtered off and washed with anhydrous 1,4-dioxane anddichloromethane. The filtrates from each tube were evaporated to drynessand the residues were each chromatographed on a silica gel column usingthe column size and the eluant shown in Table 37, to give the titlecompounds. TABLE 37 Ex. Structure MW FABMS MH⁺ Yield ChromatographicData 451

381.7 380.9 66% 15 × 2.5 cm; 0.5% Methanol in dichloromethane 452

381.7 380.9 60% 20 × 2 cm; 0.5% Methanol in dichloromethane 453

381.7 380.9 69% 15 × 2.5 cm; 0.35% Methanol in dichloromethane 454

381.7 380.9 75% 15 × 2.5 cm; 0.35% Methanol in dichloromethane 455

397.7 397.2 84% 15 × 2.5 cm; 1.5% Methanol in dichloromethane 456

397.7 457

395.7 395.0 60% 15 × 2.5 cm; 0.35% Methanol in dichloromethane 458

395.7 396.3 50% 15 × 2.5 cm; 0.35% Methanol in dichloromethane 459

395.7 396.0 76% 15 × 2.5 cm; 0.35% Methanol in dichloromethaneAdditional physical data for the compounds are given below:

Example 451

Physical properties: HRFABMS: m/z 381.0115 (MH⁺). Calcd. forC₁₅H₁₅N₄OBrCl: m/z 381.0118; [α]_(D) ^(25° C.) +1.4° (c=0.25, MeOH);δ_(H) (CDCl₃) 1.44 (3H, d, —CHCH ₃), 3.77 3.89 (1H, dd, CHCH ₂OH), (1H,dd, CHCH ₂OH), 3.94 (1H, m, CHCH₂OH), 6.41 (1H, s, H₆), 6.58 (1H, d,NH), 7.41 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.74 (1H, m, Ar—H) and 8.04ppm (1H, s, H₂); δ_(C) (CDCl₃) CH₃: 17.1; CH₂: 65.5; CH: 49.9, 88.0,127.1, 130.1, 130.2, 131.6, 143.8; C: 83.2, 132.1, 138.7, 145.6, 145.8,158.1.

Example 452

Physical properties: HRFABMS: m/z 381.0115 (MH⁺). Calcd. forC₁₅H₁₅N₄OBrCl: m/z 381.0118; [α]_(D) ^(25° C.) +6.5° (c=0.32, MeOH);δ_(H) (CDCl₃) 1.44 (3H, d, —CHCH ₃), 3.78 (1H, dd, CHCH ₂OH), 3.89 (1H,dd, CHCH ₂OH), 3.96 (1H, m, CHCH₂OH), 6.41 (1H, s, H₆), 6.58 (1H, d,NH), 7.41 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.75 (1H, m, Ar—H) and 8.04ppm (1H, s, H₂); δ_(C) (CDCl₃) CH₃: 17.1; CH₂: 65.5; CH: 49.9, 88.0,127.1, 130.1, 130.3, 131.6, 143.8; C: 83.2, 132.1, 138.6, 145.6, 145.8,158.1.

Example 453

Physical properties: HRFABMS: m/z 381.0115 (MH⁺). Calcd. forC₁₅H₁₅N₄OBrCl: m/z 381.0118; [α]_(D) ^(25° C.) +9.4° (c=0.27, MeOH);δ_(H) (CDCl₃) 1.33 (3H, d, CH₃), 2.25 (1H, bs, OH), 3.37 (1H, dd, CH₂),3.51 (1H, m, CH₂), 4.16 (1H, m, CHOH), 6.35 (1H, s, H₆), 6.93 (1H, m,NH), 7.40 (2H, m, Ar—H), 7.50 (1H, m, Ar—H), 7.70 (1H, m, Ar—H) and 8.04ppm (1H, s, H₂); δ_(C) (CDCl₃) CH₃: 20.8; CH₂: 49.2; CH: 65.7, 87.8,127.1, 130.1, 130.2, 131.2, 143.9; C: 83.1, 132.1, 138.5, 145.6, 146.6,158.3.

Example 454

Physical properties: HRFABMS: m/z 381.0112 (MH⁺). Calcd. forC₁₅H₁₅N₄OBrCl: m/z 381.0118; [α]_(D) ^(25° C.) −3.2° (c=0.29, MeOH);δ_(H) (CDCl₃) 1.32 (3H, d, CH₃), 2.48 (1H, bs, OH), 3.35 (1H, dd, CH₂),3.49 (1H, m, CH₂), 4.15 (1H, m, CHOH), 6.34 (1H, s, H₆), 6.93 (1H, m,NH), 7.39 (2H, m, Ar—H), 7.49 (1H, m, Ar—H), 7.68 (1H, m, Ar—H) and 8.03ppm (1H, s, H₂); δ_(C) (CDCl₃) CH₃: 20.8; CH₂: 49.2; CH: 65.7, 87.7,127.1, 130.1, 130.3, 131.4, 143.9; C: 83.0, 132.0, 138.6, 145.6, 146.6,158.3.

Example 455

Physical properties: HRFABMS: m/z 397.0054 (MH⁺). Calcd. forC₁₅H₁₅N₄O₂BrCl: m/z 397.0067; [α]_(D) ^(25° C.) −95° (c=0.28, MeOH);δ_(H) (CDCl₃) 3.18 (2H, bs, OH), 3.47 (1H, dd, CH₂), 3.58 (1H, dd, CH₂),3.63 (1H, dd, CH ₂OH), 3.70 (1H, dd, CH ₂OH), 3.98 (1H, m, CH), 6.35(1H, s, H₆), 7.10 (1H, m, NH), 7.37 (2H, m, Ar—H), 7.46 (1H, m, Ar—H),7.64 (1H, m, Ar—H) and 8.01 ppm (1H, s, H₂); δ_(C) (CDCl₃) CH₂: 44.7,64.0; CH: 69.7, 87.7, 127.0, 130.1, 130.3, 131.3, 143.9; C: 82.9, 132.0,138.4, 145.4, 146.7, 158.3.

Example 456

This enantiomer may be prepared by essentially the same manner asdescribed above.

Example 457

Physical properties: HRFABMS: m/z 395.0260 (MH⁺). Calcd. forC₁₆H₁₇N₄OBrCl: m/z 395.0274; [α]_(D) ^(25° C.) −34.3° (c=0.28, MeOH);δ_(H) (CDCl₃) 1.08 (3H, dd, CH₃), 1.78 (1H, m, CH₂), 1.86 (1H, m, CH₂),2.35 (1H, bs, CH₂OH), 3.71 (1H, m, CHNH), 3.81 (1H, dd, CH ₂OH), 3.90(1H, dd, CH ₂OH), 6.42 (1H, s, H₆), 6.53 (1H, m, NH), 7.41 (2H, m,Ar—H), 7.51 (1H, Ar—H), 7.75 (1H, m, Ar—H) and 8.04 ppm (1H, s, H₂);δ_(C) (CDCl₃) CH₃: 10.5; CH₂: 24.5, 63.7; CH: 55.9, 88.0, 127.1, 130.1,130.2, 131.6, 143.8; C: 83.2, 132.1, 138.6, 145.6, 146.3, 158.1.

Example 458

Physical properties: HRFABMS: m/z 395.0274 (MH⁺). Calcd. forC₁₆H₁₇N₄OBrCl: m/z 395.0274; [α]_(D) ^(25° C.) +27.5° (c=0.25, MeOH);δ_(H) (CDCl₃) 1.05 (3H, dd, CH₃), 1.76 (1H, m, CH₂), 1.85 (1H, m, CH₂),2.28 (1H, bs, CH₂OH), 3.67 (1H, m, CHNH), 3.77 (1H, dd, CH ₂OH), 3.84(1H, dd, CH ₂OH), 6.49 (1H, s, H₆), 6.66 (1H, m, NH), 7.39 (2H, m,Ar—H), 7.49 (1H, Ar—H), 7.71 (1H, m, Ar—H) and 8.04 ppm (1H, s, H₂);δ_(C) (CDCl₃) CH₃: 10.5; CH₂: 24.3, 63.3; CH: 56.1, 88.0, 127.1, 130.1,130.3, 131.5, 143.8; C: 83.0, 132.1, 138.6, 145.6, 146.3, 158.2.

Example 459

Physical properties: HRFABMS: m/z 395.0264 (MH⁺). Calcd. forC₁₆H₁₇N₄OBrCl: m/z 395.0274; δ_(H) (CDCl₃) 1.77 (2H, m, —NHCH₂CH₂CH₂CH₂OH), 1.90 (1H, bm, —NHCH₂CH₂CH₂CH₂OH), 1.93 (2H, m, —NHCH₂CH₂CH₂CH₂OH), 3.54 (2H, m, —NHCH ₂CH₂CH₂CH₂OH), 3.77 (2H, m,—NHCH₂CH₂CH₂CH ₂OH), 6.37 (1H, s, H₆), 6.72 (1H, m, —NHCH₂CH₂CH₂CH₂OH),7.41 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.75 (1H, m, Ar—H) and 8.06 ppm(1H, s, H₂); δ_(C) (CDCl₃) CH₂: 25.7, 29.7, 42.2, 62.2; CH: 87.4, 127.1,130.1, 130.2, 131.6, 143.8; C: 83.1, 132.1, 138.8, 145.6, 146.3, 158.1.

Example 4604-{[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]METHYL}PIPERIDINE-1-CARBOXYLICACID AMIDE

A.4-{[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]METHYL}PIPERIDINE-1-CARBOXYLICACID tert-BUTYL ESTER

3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (300 mg,0.875 mmoles) (prepared as described in Preparative Example 129) wasdissolved in anhydrous 1,4-dioxane (6.8 mL).4-(aminomethyl)piperidine-1-carboxylic acid tert-butyl ester (225 mg,1.05 mmoles) and diisopropyl ethylamine (0.3055 mL, 1.75 mmoles) wereadded and the mixture was heated at 75° C. for 24 h. The solution wasevaporated to dryness and the residue was chromatographed on a silicagel column (15×5 cm) using dichloromethane as the eluant to give4-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylicacid tert-butyl ester (461.2 mg, 100%): FABMS: m/z 520.1 (MH⁺); HRFABMS:m/z 520.1111 (MH⁺). Calcd. for C₂₃H₂₈N₅O₂BrCl: m/z 520.1115; δ_(H)(CDCl₃) 1.30 (2H, m, CH₂), 1.51 (9H, s, —COOC(CH₃)₃), 1.85 (2H, d, CH₂),1.95 (1H, m, CH), 2.76 (2H, m, CH₂), 3.40 (2H, m, CH₂), 6.37 (1H, s,H₆), 6.55 (1H, m, NH), 7.42 (2H, m, Ar—H), 7.52 (1H, m, Ar—H), 7.76 (1H,m, Ar—H) and 8.07 ppm (1H, s, H₂); δ_(C) (CDCl₃) CH₃: 28.5, 28.5, 28.5;CH₂: 29.1, 29.1, 43.5, 43.5, 47.9; CH: 36.3, 87.5, 127.2, 130.2, 130.3,131.6, 143.9; C: 79.7, 83.3, 132.1, 138.6, 145.4, 146.3, 154.7, 158.1.

B.[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YL]PIPERIDIN-4-YLMETHYLAMINE

4-{[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylicacid tert-butyl ester (441 mg, 0.847 mmoles) (prepared as described inExample 460, Step A above) was dissolved in methanol (4.5 mL) and 10%(v/v) conc. sulfuric acid in 1,4-dioxane (11.46 mL) was added. Themixture was stirred at 25° C. for 0.5 h. The product was worked up asdescribed in Preparative Example 241, step B and chromatographed on asilica gel column (15×5 cm) using 8% (10% conc. ammonium hydroxide inmethanol)-dichloromethane as the eluant to give[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-4-ylmethylamine(314.4 mg, 88%): FABMS: m/z 420.0 (MH⁺); HRFABMS: m/z 420.0585 (MH⁺).Calcd. for C₁₈H₂₀N₅BrCl: m/z 420.0591; δ_(H) (CDCl₃) 1.34 (2H, m, CH₂),1.86 (2H, m, CH₂), 1.91 (1H, m, CH), 2.10 (1H, bm, piperidine-NH), 2.67(2H, m, CH₂), 3.18 (2H, m, CH₂), 3.38 (2H, m, CH₂), 6.37 (1H, s, H₆),6.53 (1H, m, NH), 7.42 (2H, m, Ar—H), 7.52 (1H, m, Ar—H), 7.76 (1H, m,Ar—H) and 8.06 ppm (1H, s Ar—H); δ_(C) (CDCl₃) CH₂: 31.2, 31.2, 46.2,46.2, 48.4; CH: 36.4, 89.5, 127.1, 130.1, 130.5, 131.6, 143.8; C: 83.2,132.1, 138.9, 145.6, 146.4, 158.1.

C.4-{[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]METHYL}PIPERIDINE-1-CARBOXYLICACID AMIDE

[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-4-ylmethylamine(57 mg, 0.136 mmoles) (prepared as described in Example 460, Step Babove) was dissolved in anhydrous dichloromethane (1.2 mL) andtrimethylsilylisocyanate (0.091 mL, 0.679 mmoles) was added. The mixturewas stirred at 25° C. for 2.5 h. The mixture was diluted withdichloromethane and washed with saturated aqueous sodium bicarbonate.The organic layer was dried (MgSO₄), filtered and evaporated to dryness.The residue was chromatographed on a silica gel column (30×2.5 cm) using3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as theeluant to give4-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylicacid amide (53.7 mg, 86%): FABMS: m/z 463.1 (MH⁺); HRFABMS: m/z 463.0647(MH⁺). Calcd. for C₁₉H₂₁N₆OBrCl: m/z 463.0649; δ_(H) (d₆-DMSO) 1.09 (2H,m, CH₂), 1.63 (2H, m, CH₂), 1.87 (1H, m, CH), 2.60 (2H, m, CH₂), 3.53(2H, bm, CONH₂), 3.91 (2H, d, CH₂), 6.52 (1H, s, H₆), 7.50 (2H, m,Ar—H), 7.62 (2H, m, Ar—H), 8.33 (1H, s, H₂) and 8.52 ppm (1H, m, NH);δ_(C) (d₆-DMSO)CH₂: 30.1, 30.1, 44.2, 44.2, 47.7; CH: 36.4, 88.2, 128.1,130.7, 131.4, 132.1, 147.9; C: 82.1, 132.1, 139.4, 145.7, 147.9, 158.1,158.8.

Example 4612-{2-[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]ETHYL}PIPERIDINE-1-CARBOXYLICACID AMIDE

A.2-{2-[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]ETHYL}PIPERIDINE-1-CARBOXYLICACID tert-BUTYL ESTER

3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (400 mg,1.166 mmoles) (prepared as described in Preparative Example 129) wasdissolved in anhydrous 1,4-dioxane (5.7 mL).2-Aminoethylpiperidine-1-carboxylic acid tert-butyl ester (266 mg, 1.166mmoles) and diisopropyl ethylamine (0.409 mL, 2.33 mmoles) were addedand the mixture was heated at 75° C. for 48 h. Additional diisopropylethylamine (0.204 mL, 1.166 mmoles) was added and the heating wascontinued for a total of 58 h. The solution was evaporated to drynessand the residue was chromatographed on a silica gel column (15×5 cm)using dichloromethane followed by 0.3% (10% conc. ammonium hydroxide inmethanol)-dichloromethane as the eluant to give2-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]ethyl}piperidine-1-carboxylicacid tert-butyl ester (491.1 mg, 79%): FABMS: m/z 534.1 (MH⁺); HRESIMS:m/z 534.12797 (MH⁺). Calcd. for C₂₄H₃₀N₅O₂BrCl: m/z 534.12714; δ_(H)(CDCl₃) 1.50 (1H, m, CH₂), 1.51 (9H, s, COOC(CH₃)₃), 1.57 (2H, m, CH₂),1.68 (2H, m, CH₂), 1.76 (2H, m, CH₂), 2.24 (1H, bm, CH₂),2.82/3.40/3.54/4.08/4.51 (5H, m, CH/CH₂), 6.34 (1H, s, H₆), 7.41 (2H, m,Ar—H), 7.51 (1H, m, Ar—H), 7.76 (1H, m, Ar—H) and 8.08 ppm (1H, s, H₂);δ_(C) (CDCl₃) CH₃: 28.5, 28.5, 28.5; CH₂: 19.2, 25.5, 29.2, 29.2, 39.2,67.1; CH: ˜47.4, 87.1, 127.1, 130.1, 130.1, 131.6, 143.9; C: 80.0, 83.0,132.1, 138.9, 145.7, 146.2, 158.0.

B.[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YL]-(2-PIPERIDIN-2-YLETHYL)AMINE

2-{[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]ethyl}piperidine-1-carboxylicacid tert-butyl ester (465 mg, 0.869 mmoles) (prepared as described inExample 461, Step A above) was dissolved in methanol (4.5 mL) and 10%(v/v) conc. sulfuric acid in 1,4-dioxane (11.76 mL) was added. Themixture was stirred at 25° C. for 1.5 h. The product was worked up asdescribed in Preparative Example 241, step B and chromatographed on asilica gel column (15×5 cm) using 3.5% (10% conc. ammonium hydroxide inmethanol)-dichloromethane as the eluant to give[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-ylethyl)amine(365.6 mg, 97%): FABMS: m/z 434.1 (MH⁺); HRFABMS: m/z 434.0726 (MH⁺).Calcd. for C₁₉H₂₂N₅BrCl: m/z 434.0747; δ_(H) (CDCl₃) 1.24 (1H, m, CH₂),1.41 (1H, m, CH₂), 1.49 (1H, m, CH₂), 1.66 (1H, m, CH₂), 1.73 (1H, m,CH₂), 1.81 (1H, m, CH₂), 1.88 (2H, m, CH₂), 2.68 (1H, m, CH₂), 2.78 (1H,m, CH₂), 3.20 (1H, m, CH), 3.55 (1H, m, CH₂), 3.60 (1H, m, CH₂), 6.32(1H, s, H₆), 7.41 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.74 (1H, m, Ar—H),7.78 (1H, m, NH) and 8.05 ppm (1H, s, H₂); δ_(C) (CDCl₃) CH₂: 24.7,26.8, 33.1, 35.2, 40.3, 47.0; CH: 55.7, 87.2, 127.1, 130.0, 130.1,131.5, 143.8; C: 82.9, 132.1, 139.0, 145.7, 146.5, 158.1.

C.2-{2-[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]ETHYL}PIPERIDINE-1-CARBOXYLICACID AMIDE

[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-ylethyl)amine(200 mg, 0.46 mmoles) (prepared as described in Example 461, Step Babove) was dissolved in anhydrous dichloromethane (2 mL) andtrimethylsilylisocyanate (0.31 mL, 2.3 mmoles) was added. The mixturewas stirred at 25° C. for 1.25 h. Additional trimethylsilylisocyanate(0.155 mL, 1.15 mmoles) was added and the stirring was continued for atotal of 3 h. The mixture was diluted with dichloromethane and washedwith saturated aqueous sodium bicarbonate. The organic layer was dried(MgSO₄), filtered and evaporated to dryness. The residue waschromatographed on a silica gel column (30×2.5 cm) using 2% (10% conc.ammonium hydroxide in methanol)-dichloromethane as the eluant to give2-{2-[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]ethyl}piperidine-1-carboxylicacid amide (106.3 mg, 48%): FABMS: m/z 477.0 (MH⁺); HRFABMS: m/z477.0804 (MH⁺). Calcd. for C₂₀H₂₃N₆OBrCl: m/z 477.0805; δ_(H) (d₆-DMSO)1.29 (1H, m, CH₂), 1.52 (5H, m, CH₂), 1.72 (1H, m, CH₂), 2.05 (1H, m,CH₂), 2.51 (2H, s, CONH₂), 2.79 (1H, dd, CH), 3.31 (1H, m, CH₂), 3.34(1H, m, CH₂), 3.76 (1H, m, CH₂), 4.30 (1H, bm, CH₂), 6.42 (1H, s, H₆),7.50 (2H, m, Ar—H), 7.60 (1H, m, Ar—H), 7.63 (1H, m, Ar—H), 8.29 (1H, s,H₂) and 8.38 ppm (1H, dd, NH); δ_(C) (d₆-DMSO)CH₂: 18.6, 25.2, 28.2,38.4, 38.6, 54.8; CH: 46.7, 86.6, 127.1, 129.7, 130.3, 131.0, 143.4; C:81.2, 131.0, 138.7, 145.1, 146.4, 158.2.

Example 462

To a solution of the compound prepared in Example 204 (1.11 g, 2.12mmol) in anhydrous acetonitrile (20 mL) was added TMSI (1.70 g, 8.52mmol), dropwise at ambient temperature. After 10 minutes theacetonitrile was removed in vacuo. The resulting yellow foam was treatedwith 2 N HCl solution (7 mL) and then washed immediately with Et₂O (5×).The pH of the aqueous was adjusted to 10 with 50% NaOH (aq) and theproduct was isolated by saturation of the solution with NaCl (s)followed by extraction with CH₂Cl₂ (5×) to give the crystalline product(733 mg, 89% yield). MH⁺=387; m.p.=207.5° C.

Examples 463-472

By essentially the same procedure set forth in Example 462 onlysubstituting the compounds shown in Column 2 of Table 38, the compoundsshown in Column 3 of Table 38 were prepared. TABLE 38 Ex. Column 2Column 3 CMPD 463

MH⁺ = 403 ¹H NMR(300 MHz, CDCl₃) δ 8.52(s, 1H), 8.38(d, 1H), 8.04(s,1H), 7.78(d, 1H), 7.65(t, 1H), 6.18(s, 1H), 4.89(s, 2H), 3.26-3.21(d,2H), 2.96-2.70(m, 3H), 2.05-1.78(m, 4H). 464

MH⁺ = 454 m.p. = 175.4° C. 465

Yield = 87 MH⁺ = 470 m.p. = 220° C. m. pt (hydrochloride salt) = 164.3°C. 466

MH⁺ = 464 m.p. = 206° C. 467

MH⁺ = 411 m.p. = 169.5° C. 468

MH⁺ = 334 m.p. = 176.2° C. 469

MH⁺ = 465 m.p. = 250.4° C. 470

MH⁺ = 387 m.p. = 68.5° C. 471

MH⁺ = 387 m.p. = 59.4° C. 472

1. mp = 230-232 2. M + H = 396 472.10

1. mp = 157-160 2. M + H = 427

Example 473

Step A:

A solution of the sulfonic acid (560 mg, 1.17 mmol) in 5 mL of dry DMFwas cooled to 0° C. and SOCl₂ (278 mg, 2.34 mmol) was added. Thereaction mixture was brought to RT and stirred overnight. The next daythe contents were poured on ice and the pH was carefully adjusted to 8.The product was extracted in to EtOAc and the solvent was removed afterdrying (Na₂SO₄) to provide 240 mg (41%) of the crude sulfonyl chloridewhich was used for the next step without further purification. ¹H NMR(CDCl₃) δ 8.20-8.10 (m, 1H), 8.10-7.95 (m, 3H), 7.65 (d, 2H), 7.45-7.35(m, 1H), 7.35-7.20 (m, 1H), 7.15-7.05 (m, 1H), 6.95 (t, 1H), 4.85 (d,2H).Step B:

A solution of compound prepared in Example 473, Step A (120 mg, 0.24mmol) in 10 mL of THF was treated with 2 mL of 1 M MeNH₂ (2.00 mmol) inTHF at RT overnight. The solvent was removed and the residue waspurified by chromatography (silica, hexane:EtOAc (4:1→1:1)) to provide56 mg (48%) of the sulfonamide. ¹H NMR (DMSO-d6) δ 9.05 (t, J=9 Hz, 1H),8.35 (s, 1H), 7.90 (t, J=7.5 Hz, 1H), 7.75 (d, J=9 Hz, 2H), 7.62 (d, J=9Hz, 2H), 7.55-7.46 (m, 1H), 7.45-7.38 (m, 1H), 7.38-7.25 (m, 1H), 6.50(s, 1H), 4.80 (d, 2H), 3.30 (s, 3H) LCMS: MH⁺=492.1

Example 474

By essentially the same procedure set forth in Example 473, onlysubstituting dimethylamine, the above compound was prepared. ¹H NMR(CDCl₃) δ 8.14 (t, J=9 Hz, 1H), 8.00 (s, 1H), 7.76 (d, J=9 Hz, 2H), 7.54(d, J=9 Hz, 2H), 7.34-7.44 (m, 1H), 7.26 (t, J=9 Hz, 1H), 7.14-7.04 (m,1H), 6.93 (t, J=6 Hz, 1H), 6.45 (s, 1H), 4.75 (d, 2H), 2.70 (s, 6H)

LCMS: MH⁺=504.2

Example 475

A mixture of the compound prepared in Example 129 (300 mg, 0.66 mmol),NaOH (5 g), CH₃OH—H₂O (100 mL, 90:10) was stirred at 25 C for about 15h. Progress of hydrolysis was checked by TLC. Reaction mixture wasconcentrated to remove methanol. The concentrate was diluted with 50 mLwater, and extracted with ether to remove any un-reacted ester. Aqueoussolution, thus obtained, was neutralized with 3 N HCl to pH 4 to obtainfree acid, filtered and washed repeatedly with water. The acid was driedunder vacuum (270 mg, 93%) and used without further purification.

Example 476-479

By essentially the same procedure set forth in Example 475 onlysubstituting the compounds in Column 2 of Table 39, the compounds inColumn 3 of Table 39 were prepared. TABLE 39 Ex. Column 2 Column 3 CMPD476

Yield = 82% LCMS: MH⁺ = 365 477

Yield = 82% LCMS: MH⁺ = 379 478

Yield = 72% LCMS: MH⁺ = 393 479

Yield = 70% LCMS: MH⁺ = 407

Example 476

¹H NMR (CDCl₃) δ 8.15 (m, 2H), 8.0 (m, 1H), 7.6 (m, 1H), 7.3 (m, 2H),6.6 (s, 1H), 4.2 (d, 2H).

Example 477

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.25 (dd, 1H),7.15 (dd, 1H), 7.0 (t, 1H), 6.5 (s, 1H), 3.8 (dt, 2H), 2.6 (t, 2H).

Example 479

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.25 (dd, 1H),7.15 (dd, 1H), 6.8 (t, 1H), 3.5 (dt, 2H), 2.4 (t, 2H), 1.8 (m, 4H).

Example 480

A mixture of the acid from Example 475 (85 mg, 0.193 mmol) and Et₃N (20mg, 0.193 mmol) in THF (20 mL) was stirred at 25 C for 15 min.Isobutyryl chloroformate (28 mg, 0.205 mmol) was added to the reactionmixture and stirred for 10 min followed by addition of NH4OH solution(0.5 mL). The reaction mixture was stirred for 1 hr and concentrated todryness. The dry mass was purified by column chromatography.

Examples 481-509

By essentially the same procedure set forth in Example 480 onlysubstituting the carboxylic acid shown in Column 2 of Table 40 and theamine shown in Column 3 of Table 40, the compounds shown in Column 4 ofTable 40 were prepared. TABLE 40 Ex. Column 2 Column 3 Column 4 CMPD 481

CH₃NH₂

Yield =88% LCMS: MH⁺ =454 482

(CH₃)₂NH

Yield = 80% LCMS MH⁺ =468 483

CH₃NH₂

Yield = 70% LCMS MH⁺ =454. 484

Yield = 75% LCMS MH⁺ =482.1 485

Yield = 71% LCMS MH⁺ =480.1 486

Yield = 75% LCMS MH⁺ =494.1 487

Yield = 75% MH⁺ =494.1 488

Yield = 75% MH⁺ =496.1 489

Yield = 75% LCMS MH⁺ =508.1 490

Yield = 78% LCMS MH⁺ =524.1 491

Yield = 73% LCMS MH⁺ =508.1 492

Yield = 73% LCMS MH⁺ =510.1 493

Yield = 76% LCMS MH⁺ =526.1 494

Yield = 76% MH⁺ =523.1 495

Yield = 76% MH⁺ =523.1 496

Yield = 51% LCMS MH⁺ =484.1 497

Yield = 66% MH⁺ =537.1 498

Yield = 76% LCMS MH⁺ =551.2 499

Yield = 79% LCMS MH⁺ =552.1 500

Yield = 80% MH⁺ =549.1 501

Yield = 80% LCMS MH⁺ =478.1 502

Yield = 80% LCMH⁺ =468.1 503

Yield = 80% MH⁺ =522.1 504

Yield = 82% LCMS MH⁺ =528.1 505

CH₃NH₂

Yield = 60% MH⁺ =392 506

Yield = 60% LCMH⁺ =448.1 507

Yield = 70% MH⁺ =464.1 508

Yield = 50% LCMS MH⁺ =436.1 508.10

CH₃NH₂

Yield =92 MH⁺ =577Additional data for select examples given below:

Example 481

¹H NMR (CDCl₃) δ8.15 (dt, 1H), 8.0 (s, 1H), 7.7 (b, 2H), 7.4 (s, 1H),7.35 (m, 2H), 7.25 (d, 1H), 7.15 (dd, 1H), 6.95 (t, 1H), 6.5 (s, 1H),6.25 (bs, 1H), 4.7 (d, 2H), 3.0 (d, 3H).

Example 482

¹H NMR (CDCl₃) δ8.15 (d, 1H), 8.0 (s, 1H), 7.45-7.35 (m, 4H), 7.25 (m,2H), 7.15 (dd, 1H), 6.7 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.1 (s, 3H),3.0 (s, 3H).

Example 483

¹H NMR (CDCl₃) δ8.15 (dt, 1H), 8.0 (s, 1H), 7.8 (bs, 1H), 7.7 (d, 1H),7.5-7.3 (m, 3H), 7.25 (d, 1H), 7.15 (dd, 1H), 6.75 (t, 1H), 6.5 (s, 1H),6.2 (bs, 1H), 4.7 (d, 2H), 3.0 (d, 3H).

Example 484

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.7 (d, 2H), 7.4 (d, 2H),7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H),6.0 bs, 1H), 4.7 (d, 2H), 4.25 (m, 1H), 1.2 (d, 6H).

Example 485

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.7 (d, 2H), 7.4 (d, 2H),7.35 (s, 1H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H), 6.3(t, 1H), 4.7 (d, 2H), 2.9 (m, 1H), 0.8 (bt, 2H), 0.6 (bt, 2H).

Example 486

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.4 (d, 2H),7.35 (d, 1H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H), 6.2(t, 1H), 4.7 (d, 2H), 3.3 (dd, 2H), 1.05 (m, 1H), 0.5 (m, 2H), 0.25 (m,2H).

Example 487

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.7 (d, 2H), 7.4 (d, 2H),7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.85 (t, 1H), 6.5 (s, 1H),6.2 (bs, 1H), 4.7 (d, 2H), 4.6 (m, 1H), 2.4 (m, 2H), 1.95 (m, 1H), 1.75(m, 2H).

Example 488

¹H NMR (CDCl₃) δ 8.5 (t, 1H), 8.15 (dt, 1H), 8.0 (s, 1H), 7.7 (d, 2H),7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H),6.5 (s, 1H), 5.9 (bs, 1H), 4.7 (d, 2H), 1.4 (s, 9H).

Example 489

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.7 (d, 2H), 7.4 (d, 2H),7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H),6.0 bs, 1H), 4.7 (d, 2H), 4.4 (m, 1H), 2.05 (m, 2H), 1.7 (m, 4H), 1.4(m, 2H).

Example 490

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.7 (d, 2H), 7.4 (d, 2H),7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H),6.5 (bs, 2H), 4.7 (d, 2H), 4.1 (m, 1H), 3.9-3.7 (m, 3H), 3.3 (m, 1H),2.0-1.9 (m, 4H).

Example 491

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.45-7.35 (m, 5H), 7.25(dd, 1H), 7.1 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.7 (bs,2H), 3.3 (bs, 2H), 1.7 (bs, 4H), 1.5 (bs, 2H).

Example 492

¹H NMR (CDCl₃) δ8.15 (dt, 1H), 8.0 (s, 1H), 7.45-7.35 (m, 5H), 7.25 (dd,1H), 7.1 (dd, 1H), 6.85 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.8-3.4 (bm,8H).

Example 493

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.45-7.35 (m, 5H), 7.25(dd, 1H), 7.1 (dd, 1H), 6.80 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 4.0 (m,2H), 3.6 (m, 2H), 2.8-2.45 (m, 4H).

Example 494

¹H NMR (CH3OD) δ 8.15 (s, 1H), 8.0 (dt, 1H), 7.45-7.35 (m, 5H), 7.25(dd, 1H), 7.1 (dd, 1H), 6.80 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.7 (bs,2H), 3.4 (bs, 2H), 2.5-2.4 (m, 4H), 2.2 (s, 3H).

Example 495

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.45-7.35 (m, 5H), 7.25(dd, 1H), 7.1 (dd, 1H), 6.80 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.75(bs, 2H), 3.35 (bs, 2H), 2.4 (bs, 2H), 2.3 (s, 3H), 2.2 (bs, 2H).

Example 496

¹H NMR (CDCl₃) δ 7.95 (s, 1H), 7.9 (dt, 1H), 7.8 (t, 1H), 7.7 (d, 2H),7.15 (m, 4H), 7.05 (dd, 1H), 6.9 (dd, 1H), 6.2 (s, 1H), 4.5 (d, 2H), 3.6(t, 2H), 3.3 (dt, 2H).

Example 497

¹H NMR (CH3OD) δ 8.1 (s, 1H), 7.9 (dt, 1H), 7.8 (d, 2H), 7.5 (d, 2H),7.4 (m, 1H), 7.3 (dd, 1H), 7.2 (dd, 1H), 6.4 (s, 1H), 4.7 (d, 2H), 3.5(t, 2H), 2.7 (m, 2H), 2.6 (bs, 4H), 1.8 (bs, 4H).

Example 498

¹H NMR (CDCl₃) δ 8.5 (t, 1H), 8.15 (dt, 1H), 8.0 (s, 1H), 7.8 (d, 2H),7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H),6.5 (s, 1H), 4.7 (d, 2H), 3.7-2.5 (m, 4H), 2.35 (s, 3H), 2.2 (m, 1H),1.9-1.6 (m, 6H).

Example 499

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.4 (d, 2H),7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H),4.7 (d, 2H), 3.7 (m, 4H), 3.5 (dt, 2H), 2.6 (t, 2H), 2.5 (m, 4H).

Example 500

¹H NMR (CH3OD) δ 8.15 (s, 1H), 7.9 (dt, 1H), 7.8 (d, 2H), 7.45 (d, 2H),7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.4 (s, 1H), 4.75 (d, 2H),4.2 (m, 1H), 3.4-2.8 (m, 7H), 1.9-1.6 (m, 4H).

Example 501

¹H NMR (CDCl₃) δ 8.05 (dt, 1H), 8.0 (s, 1H), 7.6 (d, 2H), 7.4 (s, 1H),7.35 (d, 2H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H), 6.4(t, 1H), 4.7 (d, 2H), 4.2 (d, 2H), 2.3 (bs, 1H).

Example 502

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.75 (d, 2H), 7.45 (s, 1H),7.4 (d, 2H), 7.3 (dd, 1H), 7.1 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 6.1(bs, 1H), 4.7 (d, 2H), 3.5 (dq, 2H), 1.2 (t, 3H).

Example 503

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.4 (d, 2H),7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H),6.4 (t, 1H), 4.75 (d, 2H), 4.1 (m, 2H).

Example 504

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.45 (d, 2H),7.4 (m, 1H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.8 (t, 1H), 6.6 (t, 1H), 6.5(s, 1H), 4.7 (d, 1H), 3.6 (m, 2H), 2.8 (t, 2H), 2.6 (q, 2H), 1.3 (t,3H).

Example 505

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.25 (dd, 1H),7.15 (dd, 1H), 7.0 (t, 1H), 6.5 (s, 1H), 3.8 (m, 2H), 2.7 (t, 2H), 3.0(d, 3H).

Example 506

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.25 (dd, 1H),7.15 (dd, 1H), 7.0 (t, 1H), 6.5 (s, 1H), 3.8 (m, 2H), 3.6 (m, 6H), 3.4(m, 2H), 2.7 (t, 2H).

Example 507

¹H NMR (CDCl₃) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.25 (dd, 1H),7.15 (dd, 1H), 7.0 (t, 1H), 6.5 (s, 1H), 3.9 (t, 2H), 3.8 (dt, 2H), 3.7(t, 2H), 2.7 (t, 2H), 2.6 (m, 4H).

Example 508

¹H NMR (CH₃OD) δ 8.1 (s, 1H), 7.95 (dt, 1H), 7.5 (m, 1H), 7.35-7.2 (m,2H), 6.5 (s, 1H), 3.6 (m, 4H), 3.25 (m, 4H), 2.4 (t, 2H), 2.05 (dt, 2H).

Example 509

A solution of NaOH (59 mg, 1.47 mmol) in 1 mL of water was added to asuspension of NH₂OH.HCl (102 mg, 1.47 mmol) in 10 mL of methanol at 0°C. After 5 min, the compound prepared in Example 210.10 (208 mg, 0.49mmol) was added and the reaction mixture was refluxed overnight. Thesolvent was removed in vacuo and the residue was partitioned betweenwater and EtOAc. The EtOAc layer was dried (Na₂SO₄) and the solvent wasevaporated. The resulting crude amidoxime was suspended in trimethylorthoformate containing catalytic amount of PTS acid and refluxedovernight. The solvent was removed and the residue was taken up inEtOAc. The EtOAc layer washed with aq NaHCO₃ followed by water andbrine. The solvent was evaporated and the residue was purified bychromatography (silica, hexane:EtOAc (1:1)) to provide 80 mg (35%) ofthe oxadiazole. ¹H NMR (CDCl₃) δ 8.75 (s, 1H), 8.20-8.10 (m, 3H), 8.03(s, 1H), 7.53 (d, J=9 Hz, 2H), 7.45-7.36 (m, 1H), 7.30-7.22 (m, 2H),7.16-7.08 (m, 1H), 6.80 (t, J=5 Hz, 1H), 6.56 (s, 1H).

LCMS: MH⁺=465.2

Example 510

By essentially the same procedure set forth in Example 509 onlysubstituting the compound prepared in Preparative Example 192, the abovecompound was prepared. yield=75; MH⁺=453; m.p.=79.3° C.

Example 511

A mixture of the nitrile (235 mg, 0.56 mmol) and Me₃SnN₃ (343 mg, 1.67mmol) in 20 mL of dry toluene was refluxed for 2 days under Ar. Thesolvent was removed in vacuo and the residue was dissolved in drymethanol. HCl gas was bubbled through the solution for 15 min and thereaction mixture allowed to stand at overnight at RT. The next day, thesolvent was removed, the residue was taken in water and the pH wasadjusted to 5. The precipitated product was extracted into EtOAc.Evaporation of the EtOAc layer after drying (Na₂SO₄) provided theresidue which was purified by chromatography (silica, DCM:MeOH(98:2→95:5)) to yield 50 mg (19%) of the pure tetrazole. ¹H NMR (CD₃OD)δ 8.10 (s, 1H), 8.00 (d, J=9 Hz, 2H), 7.90 (t, J=7 Hz, 1H), 7.65 (d, J=9Hz, 2H), 7.50-7.40 (m, 1H), 7.30-7.10 (m, 2H), 6.45 (s, 1H), 4.80 (s,2H); LCMS: MH⁺=465.0

Example 512

By essentially the same procedure set forth in Example 511 onlysubstituting the compound prepared in Example 192, the above compoundwas prepared. Yield=64; MH⁺=453; m.p.=238.9° C.

Example 513

The compound prepared in Example 157 was dissolved in dioxane (30 mL)and a HCl-dioxane solution (4 M, 30 mL) was added. The reaction mixturewas stirred at room temperature for 4 h. The reaction mixture wasevaporated under reduced pressure and ethyl acetate (200 mL) was added.The organic solution washed with 1 N sodium hydroxide followed bysaturated brine. The organic layer was dried over anhydrous sodiumsulfate and evaporated under reduced pressure. MH⁺=442.1

Example 514-526

By essentially the same procedure set forth in Example 513, onlysubstituting the compounds shown in Column 2 of Table 41, the compoundsshown in Column 3 of Table 41 were prepared. TABLE 41 Ex. Column 2Column 3 CMPD 514

MH⁺ =420.1 515

MH⁺ =442.1 516

MH⁺ =380.1 517

MH⁺ =406.1 518

MH⁺ =380.1 519

MH⁺ =394.1 520

MH⁺ =366 521

MH⁺ =394 522

MH⁺ =408.1 523

MH⁺ =420.1 524

525

MH⁺ =420.1 526

MH⁺ =428.1 526.10

Examples 528-564

General Procedure for 5-Piperidinyl Parallel Library Formation:

To a mixture of the starting material (80 mg, 0.21 mmol) shown in Column2 of Table 42 in anhydrous CH₂Cl₂ (1.5 mL) was added DIPEA (75 μL, 0.42mmol) and the appropriate capping reagent (1.1 equiv., 0.23 mmol). After1 to 2 h, the reaction mixture was applied to 1000 micron preparatoryTLC plate and was subsequently developed using a 8-10% EtOH—CH₂Cl₂ aseluent to afford the compounds shown in Column 3 of Table 42. TABLE 42Ex. Column 2 Column 3 CMPD 528

MH⁺ =608 m.p. =230.1° C. 529

Yield =82 MH⁺ =614 m.p. =235.4° C. 530

MH⁺ =486 m.p. =60.5° C. 531

MH⁺ =500 m.p. =113.6° C. 532

MH⁺ =430 m.p. =158.3- 159.2° C. 533

MH⁺ =531 m.p. =105.9° C. 534

MH⁺ =486 535

MH⁺ =500 536

MH⁺ =430 537

MH⁺ =531 538

MH⁺ =486 m.p. =69.6° C. 539

MH⁺ =500 m.p. =82.3° C. 540

MH⁺ =430 m.p. =223.6° C. 541

MH⁺ =531 m.p. =118.1° C. 542

MH⁺ =455 m.p. =109- 110° C. 543

MH⁺ =429 m.p. =111.5° C. 544

MH⁺ =455 545

MH⁺ =429 546

MH⁺ =455 m.p. =80.1° C. 547

MH⁺ =429 m.p. =64.7° C. 548

MH⁺ =494 m.p. =76.5° C. 549

MH⁺ =493 m.p. =83.6° C. 550

MH⁺ =465 m.p. =207.5° C. 551

MH⁺ =494 552

MH⁺ =493 553

MH⁺ =465 554

MH⁺ =481 m.p. =102.7° C. 555

MH⁺ =494 m.p. =85.3° C. 556

MH⁺ =493 m.p. =89.1° C. 557

MH⁺ =465 m.p. =83.8° C. 558

Yield =quant. MH⁺ =443 m.p. =98.3° C. (HCl salt) 559

MH⁺ =454 560

Yield =quant. MH⁺ =429 m.p. =111.5- 112.6° C. 561

MH⁺ =460 m.p. =122.7° C. 562

MH⁺ =460 m.p. =95.4° C. 563

MH⁺ =460 564

MH⁺ =460 m.p. =95.4° C.Additional data for select examples given below.

Example 534

¹H NMR (300 MHz, CDCl₃) δ 8.66-8.62 (s, 1H), 8.62-8.58 (d, 1H), 7.95 (s,1H), 7.72-7.68 (d, 1H), 7.36-7.31 (dd, 1H), 6.66-6.62 (t, 1H), 5.93 (s,1H), 4.65-4.62 (d, 2H), 3.86-3.82 (d, 1H), 3.65-3.58 (m, 1H), 3.26-3.12(dd, 4H), 3.02-2.80 (m, 3H), 2.10-2.00 (m, 1H), 1.67-1.57 (m, 3H).

Example 535

¹H NMR (300 MHz, CDCl₃) δ 8.66-8.62 (s, 1H), 8.62-8.58 (d, 1H), 7.95 (s,1H), 7.72-7.67 (d, 1H), 7.36-7.30 (dd, 1H), 6.70-6.64 (t, 1H), 5.90 (s,1H), 4.63-4.61 (d, 2H), 3.93-3.86 (m, 1H), 3.69-3.61 (m, 4H), 3.27-3.23(m, 4H), 3.10-3.01 (dd, 1H), 2.93-2.84 (m, 2H), 2.08-2.03 (m, 1H),1.90-1.57 (m, 4H).

Example 536

¹H NMR (300 MHz, CDCl₃) δ 8.67 (s, 1H), 8.62-8.58 (d, 1H), 7.96 (s, 1H),7.72-7.68 (d, 1H), 7.36-7.30 (dd, 1H), 6.79-6.72 (t, 1H), 5.96 (s, 1H),4.86 (br s, 2H), 4.66-4.63 (d, 2H), 3.89-3.73 (m, 2H), 3.55-3.32 (m,2H), 3.00-2.89 (m, 1H), 2.10-1.97 (m, 2H), 1.70-1.53 (m, 2H).

Example 537

¹H NMR (300 MHz, CDCl₃) δ 8.66 (s, 1H), 8.62-8.58 (d, 1H), 7.98 (s, 1H),7.77-7.76 (t, 1H), 7.72-7.69 (d, 1H), 7.63-7.59 (m, 1H), 7.56 (s, 1H),7.36-7.29 (dd, 1H), 6.83-6.79 (t, 1H), 5.96 (s, 1H), 4.67-4.64 (d, 2H),3.98-3.93 (dd, 1H), 3.79-3.68 (m, 2H), 3.37-3.28 (m, 1H), 3.03-2.94 (m,1H), 2.12-1.99 (m, 1H), 1.76-1.56 (m, 3H).

Example 544

¹H NMR (300 MHz, CDCl₃) δ 8.66-8.62 (d, 1H), 8.61-8.58 (dd, 1H), 7.95(s, 1H), 7.72-7.67 (d, 1H), 7.36-7.30 (dd, 1H), 6.80-6.62 (br s, 1H),5.88 (s, 1H), 4.63 (s, 2H), 3.08-2.95 (m, 2H), 2.87-2.80 (m, 2H), 2.04(m, 1H), 1.85-1.78 (m, 4H), 1.52-1.44 (m, 1H), 0.87-0.82 (m, 2H),0.72-0.66 (m, 2H).

Example 545

¹H NMR (300 MHz, CDCl₃) δ 8.66 (s, 1H), 8.62-8.58 (br t, 1H), 7.97 (s,1H), 7.73-7.68 (d, 1H), 7.36-7.30 (br t, 1H), 6.79-6.72 (br t, 1H), 5.96(s, 1H), 4.64 (br s, 2H), 4.59-4.46 (br d, 1H), 3.95-3.74 (br m, 1H),3.57-3.49 (dd, 1H), 3.10-3.01 (dd, 1H), 2.86-2.70 (m, 2H), 2.13 (s, 3H),2.06-2.00 (m, 2H), 1.65-1.48 (m, 2H).

Example 551

¹H NMR (300 MHz, CDCl₃) δ 8.67 (s, 1H), 8.63-8.59 (d, 1H), 7.96 (s, 1H),7.74-7.69 (d, 1H), 7.36-7.30 (dd, 1H), 6.69-6.64 (t, 1H), 5.95 (s, 1H),4.67-4.63 (d, 2H), 3.85 3.65 (m, 1H), 3.75-3.65 (m, 1H), 3.25-3.18 (dd,1H), 3.03-2.90 (m, 2H), 2.81 (s, 6H), 2.03-1.95 (m, 1H), 1.89-1.68 (m,3H).

Example 552

¹H NMR (300 MHz, CDCl₃) δ 8.67 (s, 1H), 8.62-8.59 (d, 1H), 7.95 (s, 1H),7.74-7.69 (d, 1H), 7.36-7.31 (dd, 1H), 6.67-6.60 (t, 1H), 5.98 (s, 1H),4.67-4.63 (d, 2H), 3.92-3.86 (m, 1H), 3.85-3.75 (m, 1H), 3.40-3.30 (dd,1H), 3.27-3.16 (m, 1H), 3.10-2.86 (m, 2H), 2.10-1.78 (m, 3H), 1.40-1.30(d, 6H).

Example 553

¹H NMR (300 MHz, CDCl₃) δ 8.67 (s, 1H), 8.62 (br s, 1H), 7.96 (s, 1H),7.74-7.69 (d, 1H), 7.36-7.31 (dd, 1H), 6.70-6.66 (t, 1H), 5.98 (s, 1H),4.67-4.63 (d, 2H), 3.88-3.81 (m, 1H), 3.71-3.65 (m, 1H), 3.20-3.11 (dd,1H), 3.02-2.91 (m, 1H), 2.90-2.80 (m, 4H), 2.01-1.80 (m, 3H).

Example 559

¹H NMR (300 MHz, CDCl₃) δ 8.66-8.60 (d, 1H), 8.50-8.44 (dd, 1H), 8.01(s, 1H), 7.93 (m, 1H), 7.48-7.40 (dd, 1H), 6.08 (s, 1H), 4.80-7.74 (s,2H), 4.32-4.19 (br d, 2H), 3.10-2.86 (m, 2H), 1.95-1.68 (m, 4H).

Example 563

¹H NMR (300 MHz, CDCl₃) δ 8.66 (s, 1H), 8.62-8.58 (d, 1H), 7.96 (s, 1H),7.73-7.68 (d, 1H), 7.36-7.30 (dd, 1H), 6.96-6.86 (br s, 1H), 6.79-6.74(t, 1H), 6.00 (s, 1H), 4.67-4.64 (d, 2H), 4.37-4.30 (dd, 1H), 4.22-4.13(m, 1H), 3.97-3.86 (dd, 1H), 3.73-3.64 (m, 1H), 3.17-3.14 (d, 3H),3.07-2.99 (m, 1H), 2.20-1.97 (m, 2H), 1.68-1.48 (m, 2H).General Procedure 1: Procedure for the Amide Formation ParallelSynthesis:

Parallel synthesis was conducted in polypropylene 96-well reactionblocks with removable top seal and fixed bottom seal. Each reaction wellwas fitted with a 20 micron polypropylene bottom frit and the maximumvolume was 3 mL. Collection block was not fitted with bottom frit. Toeach reaction well was added a solution of an amine (0.021 mmol)dissolved in a DMF-THF-MeCN mixture (4:3:3 v/v, 0.95 mL), EDC resin(P-EDC, Polymer Laboratories Ltd., 43 mg, 0.063 mmol),1-hydroxybenzotriazole (HOBt, 5.67 mg, 0.042 mmol) and a solution of acarboxylic acid in dimethylformamide (1 M, 0.0315 mL, 0.0315 mmol). Thereaction mixture was agitated at room temperature for 16 h. The crudeproduct solution was filtered into a reaction well loaded with trisamineresin (P—NH2, Argonaut Tech. Inc., 30 mg, 0.126 mmol) and isocyanateresin (P—NCO, Argonaut Tech. Inc., 35 mg, 0.063 mmol). The reactionmixture was agitated at room temperature for 16 h and filtered into thecollection block. The product solution was evaporated under reducedpressure to afford the desired amide product.General Procedure 2: Procedure for the Sulfonamide Formation ParallelSynthesis

Parallel synthesis was conducted in polypropylene 96-well reactionblocks with removable top seal and fixed bottom seal. Each reaction wellwas fitted with a 20 micron polypropylene bottom frit and the maximumvolume was 3 mL. Collection block was not fitted with bottom frit. Toeach reaction well was added a solution of an amine (0.021 mmol)dissolved in a DMF-THF-MeCN mixture (3:2:2 v/v, 0.95 mL), DIEA resin(P-DIEA, Argonaut Tech. Inc., 18 mg, 0.063 mmol) and a solution of asulfonyl chloride in dimethylformamide (1 M, 0.0315 mL, 0.0315 mmol).The reaction mixture was agitated at room temperature for 16 h. Thecrude product solution was filtered into a reaction well loaded withtrisamine resin (P—NH2, Argonaut Tech. Inc., 30 mg, 0.126 mmol) andisocyanate resin (P—NCO, Argonaut Tech. Inc., 35 mg, 0.063 mmol). Thereaction mixture was agitated at room temperature for 16 h and filteredinto the collection block. The product solution was evaporated underreduced pressure to afford the desired sulfonamide product.General Procedure 3: Procedure for the Urea Formation Parallel Synthesis

Parallel synthesis was conducted in polypropylene 96-well reactionblocks with removable top seal and fixed bottom seal. Each reaction wellwas fitted with a 20 micron polypropylene bottom frit and the maximumvolume was 3 mL. Collection block was not fitted with bottom frit. Toeach reaction well was added a solution of an amine (0.021 mmol)dissolved in a DMF-MeCN mixture (1:1 v/v, 0.95 mL) and a solution of anisocyanate in dichloromethane (0.33 M, 0.126 mL, 0.042 mmol). Thereaction mixture was agitated at room temperature for 16 h. The crudeproduct solution was filtered into a reaction well loaded with trisamineresin (P—NH2, Argonaut Tech. Inc., 30 mg, 0.126 mmol) and isocyanateresin (P—NCO, Argonaut Tech. Inc., 35 mg, 0.063 mmol). The reactionmixture was agitated at room temperature for 16 h and filtered into thecollection block. The product solution was evaporated under reducedpressure to afford the desired urea product.General Procedure 4: Procedure for the Reductive Alkylation ParallelSynthesis

Parallel synthesis was conducted in polypropylene 96-well reactionblocks with removable top seal and fixed bottom seal. Each reaction wellwas fitted with a 20 micron polypropylene bottom frit and the maximumvolume was 3 mL. Collection block was not fitted with bottom frit. Toeach reaction well was added a solution of an amine (0.021 mmol)dissolved in AcOH-DCE mixture (1:99 v/v, 0.5 mL), a solution of analdehyde or ketone in dichloroethane (1 M, 0.147 mL, 0.147 mmol), and asolution of tetramethylammonium triacetoxyborohydride (11 mg, 0.042mmol) dissolved in AcOH-DCE mixture 1:99 v/v, 0.5 mL). The reactionmixture was agitated at room temperature for 3 days. The crude productsolution was filtered into a reaction well loaded with sulfonic acidresin Lanterns (P—SO₃H, MimotopesPty Ltd., 0.3 mmol). The reactionmixture was agitated at room temperature for 2 h and decanted. Theproduct resin Lanterns were washed with methanol (1 mL) for three times.A solution of ammonia in methanol (2 M, 1.2 mL) was added. The reactionmixture was agitated at room temperature for 30 min. and filtered intothe collection block. The product solution was evaporated under reducedpressure to afford the desired tertiary amine product.General Procedure 5: Procedure for the Parallel Synthesis of7,N-Substituted pyrazolo[1,5a]pyrimidines

To 3-bromo-7-chloro-5-(2-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (9.0mg, 0.03 mmol) in tetrahydrofuran were added di-iso-propylethylamine (12μL, 0.07), followed by cyclopropylmethylamine (70 μL, 0.07 mmol; 1Msolution in DMF). The reaction mixture was heated to 70° C. for 36 h andthen cooled to rt. The mixture was treated with (P—NCO, Argonaut Tech.Inc 70 mg, 0.12 mmol), and P—CO₃ ⁻ (Argonaut Tech. Inc 70 mg, 0.24 mmol)and shaken at rt for 12-18 h. The solution was filtered and evaporatedto dryness to provide the product. observed m/z 375.21.

General Procedure 6: Procedure for the Parallel Synthesis of5,N-Substituted pyrazolo[1,5a]pyrimidines

General Protocols:

Parallel synthesis was performed in a 96 well polypropylene blocks asdescribed elsewhere. In the instance that heating was required,reactions were conducted in 2.5 mL glass tubes individually sealed witha polypropylene mat and heating achieved by a 96 well heat transferblock.

Step A:

To the 3-bromo-5-chloro-7-N-Boc-alkylamino-pyrazolo[1,5-a]pyrimidine (17mg, 0.04 mmol) in p-dioxane were added DIEA (9 μL, 0.05), followed bycyclopropyl-methylamine (80 μL, 0.08 mmol; 1M solution in isopropanol).The reaction mixture was heated to 90° C. for 36 h and then cooled tort. The mixture was treated with P—NCO (Argonaut Tech. Inc. 70 mg, 0.12mmol) and P—CO₃ ⁻ (Argonaut Tech. Inc. 70 mg, 0.24 mmol) and shaken atrt for 12-18 h. The solution was filtered and evaporated to dryness toprovide the product.

Step B (Acidic):

The product from STEP A was taken up in 35% TFA/DCM and agitated for 4 hfollowed by concentration under high vacuum. The residue was treatedwith 10% HCl(aq) in MeOH agitated for 2 h and then concentrated to givethe desired product. observed m/z 375.21.

Step B (Basic):

The product from step A was taken up in EtOH and treated with Ambersep®900-OH ion exchange resin (Acros, 100 mg), heated at reflux for 48 hwith gently stirring. The reaction mixture was cooled to rt, filteredand concentrated to provide the desired product.

Example 565

By utilizing the procedure set forth in General Procedure 1 and thecompound from Example 462 shown below, the compounds with the observedm/z shown in Table 43 were prepared.

Example 566

By utilizing the procedure set forth in General Procedure 1 and thecompound from Example 471 shown below, the compounds shown in Table 44with the observed m/z were prepared.

Example 567

By utilizing the procedure set forth in General Procedure 1 and thecompound from Example 515 shown below, the compounds shown in Table 45with the observed m/z were prepared.

Example 568

By utilizing the procedure set forth in General Procedure 1 and thecompound from Example 513 shown below, the compounds shown in Table 46with the observed m/z were prepared.

Example 569

By utilizing the procedure set forth in General Procedure 1 and thecompound from Example 526 shown below, the compounds shown in Table 47with the observed m/z were prepared.

Example 570

By utilizing the procedure set forth in General Procedure 1 and thecompound from Example 524 shown below, the compounds shown in Table 48with the observed m/z were prepared.

Example 571

By utilizing the procedure set forth in General Procedure 1 and thecompound from Example 525 shown below, the compounds shown in Table 49with the observed m/z were prepared.

Example 572

By utilizing the procedure set forth in General Procedure 1 and thecompound from Example 526.10 shown below, the compounds shown in Table50 with the observed m/z were prepared.

Example 573

By utilizing the procedure set forth in General Procedure 1 and thecompound from Example 518 shown below, the compounds shown in Table 51with the observed m/z were prepared.

Example 574

By utilizing the procedure set forth in General Procedure 1 and thecompound from Example 519 shown below, the compounds shown in Table 52with the observed m/z were prepared.

Example 575

By utilizing the procedure set forth in General Procedure 1 and thecompound from Example 520 shown below, the compounds shown in Table 53with the observed m/z were prepared.

Example 576

By utilizing the procedure set forth in General Procedure 1 and thecompound from Example 522 shown below, the compounds shown in Table 54with the observed m/z were prepared.

Example 577

By utilizing the procedure set forth in General Procedure 1 and thecompound from Example 523 shown below, the compounds shown in Table 55with the observed m/z were prepared.

Example 578

By utilizing the procedure set forth in General Procedure 2 and thecompound from Example 462 shown below, the compounds shown in Table 56with the observed m/z were prepared.

Example 579

By utilizing the procedure set forth in General Procedure 2 and thecompound from Example 471 shown below, the compounds shown in Table 57with the observed m/z were prepared.

Example 580

By utilizing the procedure set forth in General Procedure 2 and thecompound from Example 515 shown below, the compounds shown in Table 58with the observed m/z were prepared.

Example 581

By utilizing the procedure set forth in General Procedure 2 and thecompound from Example 513 shown below, the compounds shown in Table 59with the observed m/z were prepared.

Example 582

By utilizing the procedure set forth in General Procedure 2 and thecompound from Example 513 shown below, the compounds shown in Table 60with the observed m/z were prepared.

Example 583

By utilizing the procedure set forth in General Procedure 2 and thecompound from Example 524 shown below, the compounds shown in Table 61with the observed m/z were prepared.

Example 584

By utilizing the procedure set forth in General Procedure 2 and thecompound from Example 525 shown below, the compounds shown in Table 62with the observed m/z were prepared.

Example 585

By utilizing the procedure set forth in General Procedure 2 and thecompound from Example 526.10 shown below, the compounds shown in Table63 with the observed m/z were prepared.

Example 586

By utilizing the procedure set forth in General Procedure 2 and thecompound from Example 518 shown below, the compounds shown in Table 64with the observed m/z were prepared.

Example 587

By utilizing the procedure set forth in General Procedure 2 and thecompound from Example 519 shown below, the compounds shown in Table 65with the observed m/z were prepared.

Example 588

By utilizing the procedure set forth in General Procedure 2 and thecompound from Example 520 shown below, the compounds shown in Table 67with the observed m/z were prepared.

Example 589

By utilizing the procedure set forth in General Procedure 2 and thecompound from Example 521 shown below, the compounds shown in Table 68with the observed m/z were prepared.

Example 590

By utilizing the procedure set forth in General Procedure 2 and thecompound from Example 523 shown below, the compounds shown in Table 69with the observed m/z were prepared.

Example 591

By utilizing the procedure set forth in General Procedure 3 and thecompound from Example 462 shown below, the compounds shown in Table 70with the observed m/z were prepared.

Example 592

By utilizing the procedure set forth in General Procedure 3 and thecompound from Example 471 shown below, the compounds shown in Table 71with the observed m/z were prepared.

Example 593

By utilizing the procedure set forth in General Procedure 3 and thecompound from Example 513 shown below, the compounds shown in Table 72with the observed m/z were prepared.

Example 594

By utilizing the procedure set forth in General Procedure 3 and thecompound from Example 524 shown below, the compounds shown in Table 73with the observed m/z were prepared.

Example 595

By utilizing the procedure set forth in General Procedure 3 and thecompound from Example 524 shown below, the compounds shown in Table 74with the observed m/z were prepared.

Example 596

By utilizing the procedure set forth in General Procedure 3 and thecompound from Example 519 shown below, the compounds shown in Table 75with the observed m/z were prepared.

Example 597

By utilizing the procedure set forth in General Procedure 3 and thecompound from Example 520 shown below, the compounds shown in Table 76with the observed m/z were prepared.

Example 598

By utilizing the procedure set forth in General Procedure 3 and thecompound from Example 521 shown below, the compounds shown in Table 77with the observed m/z were prepared.

Example 599

By utilizing the procedure set forth in General Procedure 3 and thecompound from Example 523 shown below, the compounds shown in Table 78with the observed m/z were prepared.

Example 600

By utilizing the procedure set forth in General Procedure 4 and thecompound from Example 462 shown below, the compounds shown in Table 79with the observed m/z were prepared.

Example 601

By utilizing the procedure set forth in General Procedure 4 and thecompound from Example 471 shown below, the compounds shown in Table 80with the observed m/z were prepared.

Example 602

By utilizing the procedure set forth in General Procedure 4 and thecompound from Example 525 shown below, the compounds shown in Table 81with the observed m/z were prepared.

Example 603

By utilizing the procedure set forth in General Procedure 4 and thecompound from Example 526.10 shown below, the compounds shown in Table82 with the observed m/z were prepared.

Example 604

By utilizing the procedure set forth in General Procedure 4 and thecompound from Example 521 shown below, the compounds shown in Table 83with the observed m/z were prepared.

Example 605

By utilizing the procedure set forth in General Procedure 4 and thecompound from Example 523 shown below, the compounds shown in Table 84with the observed m/z were prepared.

Example 606

By utilizing the procedure set forth in General Procedure 5 and thecompound from Preparative Example 81 shown below, the compounds shown inTable 85 with the observed m/z were prepared.

Example 607

By utilizing the procedure set forth in General Procedure 6 and thecompound from Preparative Example 196, the compounds shown in Table 86with the observed m/z were prepared.

Preparative Example 500

Piperidine-2-ethanol (127 g, 980 mmol) in 95% EtOH (260 mL) was added to(S)-(+)-camphorsulfonic acid (228.7 g, 1.0 eq.) in 95% EtOH (150 mL) andthe resulting solution was warmed to reflux. To the warm solution wasadded Et₂O (600 mL) and the solution cooled to room temperature and letstand 3 days. The resulting crystals were filtered and dried in vacuo(25 g): mp 173-173° C. (lit. 168° C.). The salt was then dissolved inNaOH (3M, 100 mL) and stirred 2 hours and the resulting solution wasextracted with CH₂Cl₂ (5×100 mL). The combined organics were dried overNa₂SO₄, filtered, filtered and concentrated under reduced pressure togive (S)-piperidine-2-ethanol (7.8 g) a portion of which wasrecrystallized from Et₂O: mp=69-70° C. (lit. 68-69° C.); [α]_(D)=14.09°(CHCl₃, c=0.2).

Preparative Example 501

Bye essentially the same procedure set forth in Preparative Example 500only substituting (R)-(−)-camphorsulfonic acid, (R)-piperidine-2-ethanolwas prepared. (1.27 g): [α]_(D)=11.3° (CHCl₃, c=0.2).

Preparative Example 502

To pressure bottle charged with a solution ofcis-(1R,2S)-(+)-2-(Benzylamino)cyclohexanemethanol (1 g, 4.57 mmol) inMeOH (35 mL) was added 20% wt Pd(OH)₂ (0.3 g, >50% wet) in one portion.The mixture was shaken under 50 psi of H₂ in a Parr hydrogenationapparatus for 12 h. The mixture was purged to N₂ and was filteredthrough a pad of Celite. The pad was generously washed with MeOH (2×25mL) and the resulting filtrate was concentrated under reduces pressureto afford 0.57 g (97%) of a white solid. M+H=130.

Preparative Example 503

Step A:

To a solution of 3-Br adduct (1.1 g, 4.1 mmol) from Preparative Example142 in THF (40 mL) at 0° C. was added CH₃SNa (0.32 g, 4.53 mmol) in oneportion. The heterogenous mixture was stirred for 72 h at rt and themixture was concentrated under reduced pressure. The crude product waspartitioned between water (10 mL) and EtOAc (30 mL) and the layers wereseparated. The organic layer washed with brine (1×10 mL) and dried(Na₂SO₄). The organic layer was filtered and concentrated under reducedpressure to afford 1.0 g (88%) of a yellow solid. mp 150-152° C.;M+H=280. This material was taken onto Step B without furtherpurification.

Step B:

To a solution of thiomethyl derivative (1.5 g, 5.37 mmol) from Step A indioxane/DIPEA (15 mL/4 mL) at rt was added amino alcohol (1.3 g, 8.06mmol) from Preparative Example 10. The mixture was heated at reflux for48 h, cooled to rt, and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography using CH₂Cl₂/MeOH (30:1) aseluent to afford 1.8 g of product (90%) as a yellow crystalline solid.mp 167-169° C.; M+H=373.

Step C:

To a solution of thiomethyl derivative (2.2 g, 5.92 mmol) from Step B inCH₂Cl₂ (20 mL) at 0° C. was added MCPBA (1.53 g, 8.9 mmol) in oneportion. The resulting mixture was stirred for 2 h at 0° C. whereuponthe mixture was diluted with CH₂Cl₂ (20 mL) and sat. aq. NaHCO₃ (15 mL).The layers were separated and the organic layer washed with sat. aq.NaHCO₃ (15 mL) and brine (1×15 mL). The organic layer was dried(Na₂SO₄), filtered, and concentrated under reduced pressure to afford2.0 g of a brown solid (87%). mp 181-183° C.; M+H=388.

Preparative Example 504

The title compound (racemic) was prepared according to the procedure setforth in Preparative Example 503 except substituting the commerciallyavailable cis-hydroxymethyl-1-cyclohexylamine hydrochloride in Step B.

Preparative Example 505

Step A:

Treatment of thiomethyl derivative (2.0 g, 7.2 mmol) from Step A ofPreparative Example 503 with (S)-piperidine-2-ethanol (1.2 g, 9.3 mmol)from Preparative Example 500 under the identical conditions as describedin Step B of Preparative Example 503, 0.90 g (34%) of the title compoundwas prepared semisolid. mp 173-175° C. M+H=372.

Step B:

Following the procedure from Step C in Preparative Example 503, thethiomethyl derivative (0.30 g, 0.81 mmol) was treated with MCPBA (0.21g, 1.2 mmol) to afford 0.31 g (99%) the title compound as a yellowviscous oil. M+H=388.

Preparative Example 506

The title compound (racemic) was prepared according to the procedure setforth in Preparative Example 505 except substituting the commerciallyavailable piperidine-2-ethanol. M+H=388.

Preparative Example 507

t-BuOK (112.0 g, 1.00 mol) was stirred under N₂ in dry Et₂O (3.0 L) in a5 L flask equipped with an addition funnel. A mixture of butyronitrile(69.0 g, 1.00 mol) and ethylformate (77.7 g, 1.05 mol) was addeddropwise during 3 hrs, the reaction mixture was then stirred overnightat room temperature. The mixture was cooled to 0° C., AcOH (57 mL) wasadded, the mixture was filtered, and the solid washed with Et₂O (500mL). The combined filtrates were evaporated at room temperature on arotovap to give pale yellow oil (95.1 g).

The oil was dissolved in dry EtOH (100 mL), 99% hydrazine monohydrate(48 mL) was added, then AcOH (14 mL) was added, and the mixture wasrefluxed under N₂ overnight. The solvents were evaporated and theresulting oil was chromatographed on silica gel with CH₂Cl₂:7N NH₃ inMeOH. 22.4 g (20%) of 3-amino-4-ethylpyrazole was obtained as clear oilthat solidified upon standing.

Preparative Example 508

Step, A:

The pyrazole from Preparative Example 507 (9.80 g) and dimethylmalonate(45 mL) were stirred and refluxed under N₂ for 3 hrs. The excess ofdimethylmalonate was evaporated in a vacuum and the residue waschromatographed with 15:1 CH₂Cl₂:MeOH to yield pale yellow solid (10.6g, 57%). LCMS: MH⁺=212.Step B:

Dry MeOH (200 mL) was added under N₂ to a mixture of the amide from StepA (11.9 g, 56.4 mmol) and sodium methoxide (4.57 g, 84.6 mmol). Themixture was stirred and refluxed under N₂ for 5 hrs, cooled to rt, andconc. HCl (20 mL) was added. The solvents were evaporated and theresidue was suspended in H₂O (300 mL). The solid was filtered off,washed on filter with 2×300 mL of H₂O, and dried in a vacuum at 100° C.7.40 g (73%) of cream-colored solid was obtained. LCMS: MH⁺=180.Step C:

POCl₃ (100 mL) and N,N-dimethylaniline (20 mL) were added under N₂ tothe diketone from Step B (7.70 g), and the mixture was stirred andrefluxed for 20 hrs under N₂. Then it was cooled to rt, carefully pouredonto 1 L of crushed ice, and extracted with EtOAc (2×500 mL). Theextracts were washed with H₂O (500 mL), dried over Na₂SO₄, filtered, andthe solvent was evaporated. The residue was chromatographed with CH₂Cl₂to yield pale yellow solid (8.20 g, 90%). LCMS: MH⁺=216.

Preparative Example 508.10

By essentially the same procedure set forth in Preparative Example 508,only substituting the compound from Preparative Example 1, the abovecompound was prepared. LCMS: MH⁺=228.

Preparative Example 509

A mixture of the dichloride from Preparative Example 508 (3.13 g, 14.5mmol), the amine.HCl from Preparative Example (3.00 g, 18.9 mmol), DIPEA(7.5 mL), and dry NMP (40 mL) plus dry dioxane (40 mL) was stirred at60° C. for 4 days under N₂. The solvents were then distilled off in avacuum and the residue was chromatographed with 6:1 EtOAc:MeOH and thenrechromatographed with 12:1 CH₂Cl₂:MeOH. So obtained solid was suspendedin H₂O (100 mL), filtered, washed on filter with H₂O (2×100 mL), anddried in a vacuum. Pale rose solid (2.37 g, 54%) was obtained. M+H=304.

Preparative Examples 510-516

By essentially the same procedure set forth in Preparative Example 509only substituting the amines in Column 2 of Table 500 and the chloridesshown in Column 3 of Table 500, the compounds shown in Column 4 of Table500 were prepared. TABLE 500 Prep. Ex. Column 2 Column 3 Column 4 CMPD510

M + H = 316 512

M + H = 318 513

M + H = 318 514

515

M + H = 332 516

Preparative Example 517

By essentially the same procedure set forth in Preparative Example 184only substituting the amines in Column 2 of Table 501, the compoundsshown in Column 3 of Table 501 were prepared. TABLE 501 Prep. Ex. Column2 Column 3 CMPD 518

M + H =422.1 519

Preparative Examples 520-521

By essentially the same procedure set forth in Preparative Example 192only substituting the compounds in Column 2 of Table 502, the compoundsshown in Column 3 of Table 502 were prepared. TABLE 502 Prep. Ex. Column2 Column 3 CMPD 520

M + H =522.1 521

M + H =539.1

Example 1000

A mixture of the compound prepared in Preparative Example 509 (1.50 g,4.94 mmol) with the aminoalcohol from Preparative Example 500 (1.91 g,14.8 mmol) in dry NMP (3 mL) was stirred under N₂ at 160° C. for 48 hr.The NMP was distilled off in a vacuum and the residue waschromatographed first with 5:1 EtOAc:MeOH, then the crude product wasrechromatographed with 10:1 CH₂Cl₂:MeOH. White solid (460 mg, 24%) wasobtained. LCSM: MH⁺=397; mp=113-115° C.

Example 1001

Major side product isolated (540 mg, 29%) was deoxygenated product(LCMS: MH⁺=381; mp=49-52° C.:

Examples 1002-1014

By essentially the same procedure set forth in Example 1000 onlysubstituting the amines in Column 2 of Table 1000 and the chlorides inColumn 3 of Table 1000 the compounds in column 4 of Table 1000 wereprepared. TABLE 1000 Ex. Column 2 Column 3 Column 4 CMPD 1002

MH⁺ = 409; mp = 165-171° C. 1003

MH⁺ = 397; mp = 219-221° C. 1004

MH⁺ = 409; mp = 138-142° C. 1005

MH⁺ = 411; mp = 194-196° C. 1006

MH⁺ = 411; mp = 118-120° C. 1007

MH⁺ = 411; mp = 85-87° C. 1008

MH⁺ = 411; mp = 105-108° C. 1009

MH⁺ = 397; mp = 173-177° C. 1010

MH⁺ = 397; mp = 169-173° C. 1011

MH⁺ = 425 1012

MH⁺ = 425; mp = 232-234° C. 1013

1014

Example 1015

To a solution of sulfoxide from Preparative Example 505 (0.10 g, 0.28mmol) in n-BuOH in a sealed tube was added Et₃N (0.13 mL, 1.0 mmol)followed by the amine dihydrochloride (0.13 g, 0.65 mmol) fromPreparative Example 216. The tube was sealed and was heated to 100° C.,cooled to room temperature, and was concentrated under reduced pressure.The crude residue was purified by preparative TLC (6×1000 μM) elutingwith CH₂Cl₂/MeOH (20:1) to afford 50 mg (40%) of a pale white solid. mp182-185° C.; M+H=446.

Examples 1016-1026

By essentially the same procedure set forth in Example 1015 onlysubstituting the sulfoxide shown in Column 2 of Table 1001 and the aminein Column 3 of Table 1001, the compounds shown in Column 4 of Table 1001were prepared. TABLE 1001 Ex. Column 2 Column 3 Column 4 CMPD 1016

mp = 182- 185° C.; M + H = 448 1017

mp = 187- 189° C.; M + H = 445 1018

mp = 139- 143° C.; M + H = 453 1020

mp = 186- 189° C.; M + H = 485 1021

mp = 154- 157° C.; M + H = 448 1022

mp = 103- 105° C.; M + H = 485 1023

mp = 203- 205° C.; M + H = 432 1024

mp = 210- 212° C.; M + H = 395 1025

mp = 82-84° C.; M + H = 446 1026

mp = 86-90° C.; M + H = 462

Examples 1027-1038

By essentially the same conditions set forth in Example 341, Steps A andB only substituting the amines in Column 2 of Table 1002 and thecompound prepared in Preparative Example 193.10, the compounds in Column4 of Table 1002 were prepared. TABLE 1002 Ex. Column 2 Column 4 CMPD1027

mp = 160- 163° C.; M + H = 434 1028

mp = 122- 124° C.; M + H = 434 1029

mp = 153- 156° C.; M + H = 408 1030

mp = 170- 174° C.; M + H = 448 1031

mp = 166- 169° C.; M + H = 434 1032

mp = 167- 168° C.; M + H = 434 1033

MH⁺ = 393 1034

mp = 157- 160° C.; M + H = 447 1035

mp = 164- 168° C.; M + H = 448 1036

mp = 165- 168° C.; M + H = 448 1037

mp = 131- 135° C.; M + H = 447 1038

Preparative Examples 1039-1041

By essentially the same procedure set forth in Example 340 onlysubstituting the amines in Column 2 of Table 1003, the compounds shownin Column 4 of Table 1003 were prepared. TABLE 1003 Ex. Column 2 Column4 CMPD 1039

mp = 210-212° C.; M + H = 392 1040

mp = 128-130° C.; M + H = 432 1041

mp = 148-151° C.; M + H = 18

Preparative Examples 1042-1057

By essentially the same procedure set forth in Example 340 only usingthe appropriate 5-chloroderivative and substituting the amines in Column2 of Table 1004, the compounds shown in Column 4 of Table 1004 wereprepared. TABLE 1004 Ex. Column 2 Column 4 CMPD 1042

M + H = 500.3 1043

M + H = 514.1 1044

M + H = 460.3 1045

M + H = 477.1 1046

M + H = 505.1 1047

M + H = 505.1 1048

M + H = 531.1 1049

M + H = 477.1 1050

M + H = 505.1 1051

M + H = 505.1 1052

M + H = 531.1 1053

M + H = 514.1 1054

M + H = 488.3 1055

M + H = 488.3 1056

M + H = 488.1 1057

M + H = 488.1

Preparative Example 10-K

SOCl₂ (18.5 mL) was added slowly under N₂ to a stirred mixture of theacid (50.0 g, 218 mmol) and pyridine (44.0 mL) in anhydrous CH₂Cl₂ (60mL). The mixture was stirred at 25° C. for 20 min, then Meldrum's acid(35.0 g, 243 mmol) and DMAP (66.6 g, 546 mmol) were added and themixture was stirred under N₂ for 1 hr. Then Et₂O (2 L) was added, themixture washed with 1 M HCl (3×500 mL), brine (500 mL), and the organiclayer was dried over Na₂SO₄, filtered, and the solvent was evaporated.The residue was dissolved in MeOH (580 mL), and the mixture was refluxedfor 4 hr. The solvent was evaporated and the residue was purified bycolumn chromatography on silica gel with 10:1 CH₂Cl₂/EtOAc as eluent.Pale yellow oil (26.5 g, 43%) was obtained.

Preparative Examples 10-K-40-K

By essentially same procedure set forth in Preparative Example 10-K, thecompounds given in Column 2 of Table 10-K were prepared. TABLE 10-KPrep. Ex. Column 2 20-K

30-K

40-K

Preparative Example 100-K

A mixture of the b-ketoester from Preparative Example 10-K (20.0 g, 70.1mmol) and 3-aminopyrazole (5.40 g, 65.0 mmol) in anhydrous toluene (60mL) was stirred and refluxed under N₂ for 24 hr. The solvent wasevaporated and the residue was purified by column chromatography onsilica gel with 20:1 CH₂Cl₂/MeOH as eluent. White solid (15.0 g, 73%)was obtained. LC-MS: 319 [M+H].

Preparative Example 101-K-104-K

By essentially same procedure set forth in Preparative Example 100-K,combining 3-aminopyrazole with the corresponding β-ketoesters, compoundsgiven in Column 2 of Table 100-K were prepared. TABLE 100-K Prep. Ex.Column 2 101-K

102-K

103-K

104-K

Preparative Example 200-K

A mixture of the product from Preparative Example 100-K (12.50 g, 39.3mmol), N,N-dimethylaniline (15.5 mL), and POCl₃ (125 mL) was stirred at25° C. for 4 days. Excess of POCl₃ was evaporated and the residue waspoured into saturated aqueous NaHCO₃ (600 mL). The mixture was extractedwith CH₂Cl₂ (3×200 mL), the combined extracts were dried over Na₂SO₄,filtered, and the solvent was evaporated. The residue was purified bycolumn chromatography on silica gel with 8:1 CH₂Cl₂/EtOAc as eluent.Pale yellow wax (9.41 g, 71%) was obtained. LC-MS: 337 [M+].

Preparative Example 201-K-204-K

By essentially same procedure set forth in Preparative Example 200-K,compounds given in Column 2 of Table 200-K were prepared. TABLE 200-KPrep. Ex. Column 2 201-K

202-K

203-K

204-K

Preparative Example 300-K

A solution of NBS (4.03 g, 22.7 mmol) in anhydrous CH₃CN (40 mL) wasadded under N₂ to a stirred solution of the product from PreparativeExample 200-K (7.63 g, 22.7 mmol) in anhydrous CH₃CN (60 mL) and CH₂Cl₂(20 mL). The mixture was stirred for 2 hr, the solvents were evaporated,and the residue was purified by column chromatography on silica gel with20:1 CH₂Cl₂/EtOAc as eluent. Pale yellow solid foam (9.20 g, 97%) wasobtained. LC-MS: 417 [M+H].

Preparative Example 301-K-304-K

By essentially same procedure set forth in Preparative Example 300-Konly substituting the compounds shown in Column 2 of Table 300-K, thecompounds given in Column 3 of Table 300-K were prepared. TABLE 300-KPrep. Ex. Column 2 Column 3 301-K

302-K

303-K

304-K

Preparative Example 303-K

By essentially the same procedure set forth in Preparative Example 300-Konly substituting N-iodosuccinimide the above compound was prepared.

Preparative Example 400-K

A mixture of the product from Preparative Example 300-K (8.00 g, 19.3mmol) and MeONa (2.16 g, 40.0 mmol) in anhydrous MeOH (100 mL) wasstirred for 20 hr. CH₂Cl₂ (200 mL) was then added, the mixture wasfiltered through Celite, the solvent was evaporated, and the residue waspurified by column chromatography on silica gel with 2:1 CH₂Cl₂/EtOAc aseluent. White solid (7.75 g, 98%) was obtained.

Preparative Examples 401-K-405-K

By essentially the same procedure set forth in Preparative Example400-K, only substituting the compound shown in Column 2 of Table 400-K,the compounds shown in Column 3 of Table 400-K were prepared. TABLE400-K Prep. Ex. Column 2 Column 3 401-K

402-K

403-K

404-K

405-K

Preparative Example 500-K

A mixture of the product from Preparative Example 400-K (600 mg, 1.46mmol), 2-thienylboronic acid (230 mg, 1.80 mmol), Pd[PPh₃]₄ (160 mg,0.14 mmol), and Na₂CO₃ (466 mg, 4.40 mmol) in 1,2-dimethoxyethane (20mL) and H₂O (4 mL) was stirred and refluxed under N₂ for 20 hr. Thesolvents were evaporated and the residue was purified by columnchromatography on silica gel with 2:1 CH₂Cl₂/EtOAc as eluent. Paleyellow solid (355 mg, 59%) was obtained. LC-MS: 415 [M+].

Preparative Examples 501-511-K

By essentially same procedure set forth in Preparative Example 500-Konly substituting the appropriate boronic acid, the compounds given inColumn 2 of Table 500-K were prepared. TABLE 500-K Prep. Ex. Column 2Data 501-K

LCMS: MH⁺ = 373 502-K

LCMS: MH⁺ = 415 503-K

LCMS: MH⁺ = 409 504-K

LCMS: MH⁺ = 555 505-K

LCMS: MH⁺ = 429 506-K

507-K

LCMS: MH⁺ = 399 508-K

LCMS: MH⁺ = 410 510-K

LCMS: MH⁺ = 425 511-K

LCMS: MH⁺ = 452

Preparative Example 520-K

A mixture of the product from Preparative Example 400-K (1.23 g, 3.00mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)1-H-pyrazole (850mg, 4.00 mmol), Pd[PPh₃]₄ (348 mg, 0.30 mmol), and Na₂CO₃ (1.27 g, 12.0mmol) in 1,2-dimethoxyethane (36 mL) and H₂O (7.5 mL) was stirred andrefluxed under N₂ for 20 hr. The solvents were evaporated and theresidue was purified by column chromatography on silica gel with 20:1EtOAc/MeOH as eluent. Pale orange solid (740 mg, 60%) was obtained.LC-MS: 413 [M+H].

Preparative Example 530-K-533-K

By essentially same procedure set forth in Preparative Example 520-K,the compounds shown in Column 2 of Table 530-K were prepared. TABLE530-K Prep. Ex. Column 2 Data 530-K

LC-MS: 429 [M + H]. 531-K

532-K

533-K

Preparative Example 550-K

A mixture of the compound from Preparative Example 512-K (230 mg, 0.50mmol), tributylphenyltin (235 mg, 0.60 mmol), and Pd[PPh3]4 (58 mg, 0.05mmol) in anhydrous dioxane (5 mL) was stirred under N2 at 90° C. for 3hr. The solvent was evaporated and the residue was purified by columnchromatography on silica gel with 20:1 CH₂Cl₂/EtOAc as eluent. Paleyellow wax (46 mg, 21%) was obtained. LC-MS: 433 [M+].

Preparative Examples 551-K-552-K

By essentially same procedure set forth in Preparative Example 550-K,only substituting the appropriate tributyltin reagent, the compoundsgiven in Column 2 of Table 550-K were prepared. TABLE 550-K Prep. Ex.Column 2 Data 551-K

LCMS: MH⁺ = 371 552-K

LCMS: MH⁺ = 416

Preparative Example 600-K

A mixture of the product from Preparative Example 500-K (350 mg, 0.85mmol), 2.0 M NH₃ in 2-propanol (7.5 mL), and conc. aqueous NH₄OH (0.75mL) was stirred in a closed pressure vessel at 75° C. for 3 days. Thesolvents were evaporated and the residue was purified by columnchromatography on silica gel with 50:1 CH₂Cl₂/MeOH as eluent. Paleyellow solid (143 mg, 42%) was obtained. LC-MS: 400 [M+].

Preparative Example 601-K-615-K

By essentially same procedure set forth in Preparative Example 600-Konly substituting the compounds in Column 2 of Table 600-K, thecompounds given in Column 3 of Table 600-K were prepared. TABLE 600-KPrep. Ex. Column 2 Column 3 Data 601-K

LCMS: MH⁺ = 359 602-K

LCMS: MH⁺ = 400 603-K

604-K

LCMS: MH⁺ = 540 605-K

LCMS: MH⁺ = 414 606-K

LCMS: M⁺ = 434 607-K

LCMS: MH⁺ = 414 608-K

LCMS: MH⁺ = 356 609-K

LCMS: MH⁺ = 418 610-K

LCMS: MH⁺ = 401 611-K

LCMS: MH⁺ = 398 612-K

LCMS: MH⁺ = 384 613-K

LCMS: MH⁺ = 395 614-K

LCMS: MH⁺ = 425 615-K

LCMS: MH⁺ = 437 616-K

617-K

618-K

Preparative Example 650-K

A mixture of the product from Preparative Example 201-K (100 mg, 0.37mmol), 2.0 M NH₃ in 2-propanol (2.0 mL), and conc. aqueous NH₄OH (0.2mL) was stirred in a closed pressure vessel at 50° C. for 2 days. Thesolvents were evaporated and the residue was purified by columnchromatography on silica gel with 30:1 CH₂Cl₂/MeOH as eluent. Whitesolid (38 mg, 41%) was obtained. LC-MS: 257 [M+2H].

Preparative Example 660-K

A mixture of the starting material (2.16 g, 10.0 mmol), 2.0 M NH₃ in2-propanol (50.0 mL), and conc. aqueous NH₄OH (10.0 mL) was stirred in aclosed pressure vessel at 50° C. for 2 days. The solvents wereevaporated, the solid was suspended in H₂O (100 mL), filtered, washed onfilter with H₂O (100 mL), and dried in a vacuum at 100° C. Slightlybeige solid (1.80 g, 91%) was obtained.

Preparative Example 661-K

By essentially same procedure set forth in Preparative Example 660-K,compound given below was prepared.

Preparative Example 662-K

A mixture of the product from Preparative Example 660-K (600 mg, 3.05mmol), the amine (837 mg, 4.50 mmol), and NaHCO₃ (756 mg, 9.00 mmol) inanhydrous N-methylpyrrolidone (4 mL) was stirred under N₂ at 140° C. for18 hr. The mixture was cooled to 25° C., CH₂Cl₂ (15 mL) was added andthe mixture was filtered. The solvents from the filtrate were distilledoff and the residue was purified by column chromatography on silica gelwith 2:1 CH₂Cl₂/EtOAc as eluent. White solid (1.01 g, 95%) was obtained.

Preparative Example 663-K

By essentially same procedure set forth in Preparative Example 662-K,compounds given below were prepared.

LC-MS: 401 [M+H].

Preparative Example 664-K

A solution of NBS (142 mg, 0.80 mmol) in anhydrous CH₃CN (5 mL) wasadded under N₂ to a stirred solution of the product from PreparativeExample 662-K (400 mg, 0.90 mmol) in anhydrous CH₃CN (5 mL) and CH₂Cl₂(5 mL). The mixture was stirred for 18 hr, the solvents were evaporated,and the residue was purified by column chromatography on silica gel with3:1 CH₂Cl₂/EtOAc as eluent. White solid (330 mg, 67%) was obtained.

Preparative Example 665-K

By essentially same procedure set forth in Preparative Example 664-K,compound given below was prepared.

Preparative Example 700-K

A solution of Br₂ (16 mg) in CH₂Cl₂ (0.5 mL) was added under N₂ to astirred solution of the product from Preparative Example 600-K (40 mg,0.10 mmol) in t-BuNH₂ (2.0 mL). The mixture was stirred for 1 hr, thesolvents were evaporated, and the residue was purified by columnchromatography on silica gel with 10:1 CH₂Cl₂/EtOAc as eluent. Off-whitesolid (18 mg, 38%) was obtained. LC-MS: 480 [M+H].

Preparative Example 701-712-K

By essentially the same procedure set forth in Preparative Example 700-Konly substituting the compounds in Column 2 of Table 700-K, thecompounds in Column 3 of Table 700-K were prepared. TABLE 700-K Prep.Ex. Column 2 Column 3 Data 701-K

LCMS: MH⁺ = 702-K

703-K

LCMS: MH⁺ = 704-K

LCMS: M⁺ = 705-K

LCMS: MH⁺ = 706-K

LCMS: MH⁺ = 707-K

LCMS: M⁺ = 479 708-K

LCMS: M⁺ = 476 709-K

LCMS: M⁺ = 462 710-K

LCMS: M⁺ = 473 711-K

LCMS: M⁺ = 503 712-K

LCMS: M⁺H = 517 713-K

714-K

715-K

Preparative Example 750-K

A solution of N-chlorosuccinimide (23 mg, 0.17 mmol) in anhydrous CH₃CN(2 mL) was added under N₂ to a stirred solution of the product fromPreparative Example 611-K (73 mg, 0.17 mmol) in anhydrous CH₃CN (2 mL).The mixture was stirred for 24 hr, the solvents were evaporated, and theresidue was purified by column chromatography on silica gel with 1:1CH₂Cl₂/EtOAc as eluent. White solid (54 mg, 68%) was obtained. LC-MS:432 [M+].

Preparative Example 800-K

To a solution of dichloride (3.0 g, 16.0 mmol) prepared as describedearlier in THF (25 mL) was added NaSMe (1.1 g, 16.0 mmol) in oneportion. The resulting mixture was stirred for 12 h at rt and wasconcentrated under reduced pressure. The crude product was partitionedbetween EtOAc (150 mL) and H₂O (30 mL) and the layers were separated.The organic layer washed sequentially with H₂O (2×30 mL) and brine (1×30mL). The organic layer was dried (Na₂SO₄), filtered, and concentratedunder reduced pressure to afford 3.0 g (94% yield) of a tan solid.LC-MS: 200.1 [M+H], purity 99%.

Preparative Example 900-K

Prepared the procedure outlined in Preparative Example 800-K exceptstarting with the dichloride shown above (7.4 g, 27.7 mmol) prepared asdescribed earlier and NaSMe (2.1 g, 30.5 mmol) afforded 7.4 g (96%yield) of the title compound as a light orange solid. LC-MS: 278.1[M+H], purity 95%.

Preparative Example 1000-K

To a solution of thiomethyl derivative from Preparative Example 800-K(1.5 g, 7.5 mmol) in H₂SO₄ (9 mL) at 0° C. was added 60% HNO₃ (4.5 mL)dropwise. The resulting solution was stirred for 2 h at 0° C. and 2 h atrt. The reaction mixture was poured into beaker containing ice (˜15 g)and the heterogeneous mixture was stirred for 45 min. The resulting pptwas collected by filtration and washed sequentially with H₂O (2×3 mL)and Et₂O (2×3 mL). The ppt was placed under high vacuum to remove tracevolatiles to afford 1.1 g (60%) of an orange solid. LC-MS: 245.0 [M+H],purity 90%.

Preparative Example 1100-K

To a solution of thiomethyl derivative (0.20 g, 1.0 mmol) fromPreparative Example 800-K in CH₂Cl₂ (5 mL) at 0° C. was added AlCl₃(0.70 g, 5.3 mmol) followed by benzoyl chloride (0.40 mL, 3.5 mmol). Themixture was heated at reflux for 12 h at rt whereupon the mixture wascarefully quenched at 0° C. with sat. aq. NaHCO₃ (3 mL). CH₂Cl₂ (5 mL)was added, the layers were separated, and the aqueous layer wasextracted with CH₂Cl₂ (2×5 mL). The organic layers were combined, washedwith brine (1×5 mL), dried (Na₂SO₄), filtered, and concentrated underreduced pressure to afford 0.27 g (88% crude yield) of a brown solid.LC-MS: 304.0 [M+H], purity 85%.

Preparative Example 1200-K

To a solution of thiomethyl derivative (0.4 g, 1.63 mmol) fromPreparative Example 1000-K in dioxane/DIPEA (7 ml/2 mL) at roomtemperature was added (S)-(−)-3-(Boc-amino)pyrrolidine (0.36 g, 1.96mmol) in a single portion. The mixture was stirred at reflux for 12 hand was cooled to rt. The mixture was filtered and washed with CH₂Cl₂(2×2 mL) and Et₂O (2×2 mL). The resultant ppt was dried under vacuum toafford 0.57 g (90% yield) of a yellow solid. LC-MS: 395.1 [M+H], purity90%.

Preparative Example 1300-K

The above compound was prepared according to the procedure outlined inPreparative Example 1200-K utilizing thiomethyl derivative fromPreparative Example 1000 (66 mg, 0.27 mmol) and(S)-(−)-1-(Boc-amino)pyrrolidine (65 mg, 0.35 mmol) to afford 83 mg (77%yield) of a yellow solid. LC-MS: 395.1 [M+H], purity 99%.

Preparative Example 1400-K

The title compound was prepared according to the procedure outlined inPreparative Example 1200-K utilizing thiomethyl derivative (0.30 g, 1mmol) from Preparative Example 1100-K and(S)-(−)-1-(Boc-amino)pyrrolidine (0.24 g, 1.3 mmol) to afford 160 mg(35% yield) of a yellow solid. LC-MS: 454.1 [M+H], purity 60%.

Preparative Example 1500-K

To a solution of thiomethyl adduct (0.17 g, 0.42 mmol) from PreparativeExample 1200-K in CH₂Cl₂ (2 mL) at 0° C. was added MCPBA (0.11 g, 0.63mmol) in one portion. The mixture was stirred for 2 h at 0° C. and 1 hat rt whereupon an additional portion of MCPBA (54 mg, 0.32 mmol) wasadded. The mixture was stirred for 2 h at rt where upon CH₂Cl₂ (3 mL)and sat. aq. NaHCO₃ (3 mL) were added. The layers were separated and theaqueous layer was extracted with CH₂Cl₂ (2×5 mL). The organic layerswere combined and washed with brine (1×3 mL). The organic layer wasdried (Na₂SO₄), filtered, and concentrated under reduced pressure toafford 0.17 (98% crude yield) of a yellow solid. This material was useddirectly without further purification. LC-MS: 411.1 [M+H], purity 85%.

Preparative Example 1600-K

The title compound was prepared according to the procedure outlined inPreparative Example 1500-K utilizing thiomethyl derivative (82 mg, 0.21mmol) from Preparative Example 1300-K 0 to afford 84 mg (98% yield) of ayellow solid. This material was used directly without furtherpurification. LC-MS: 411.1 [M+H], purity 89%.

Preparative Example 1700

The title compound was prepared according to the procedure outlined inPreparative Example 1500-K utilizing thiomethyl derivative (0.15 g, 0.33mmol) from Preparative Example 1400-K to afford 152 mg (98% yield) of ayellow solid. This material was used directly without furtherpurification. LC-MS: 470.1 [M+H], purity 40%.

Preparative Example 1800-K

To a pressure tube charged with a stir bar was added sulfoxide (0.15 g,0.36 mmol) from Preparative Example 1500-K followed by 2M NH₃ in IPA (4mL) and conc. NH₄OH (1 mL). The tube was capped and was heated to 85° C.and stirred for 14 h. The mixture was cooled to room temperature,concentrated under reduced pressure, and placed under high vacuum toremove trace volatiles. The crude product was purified by preparativethin-layer chromatography (4×1000 μM) plates using a 20:1 mixture ofCH₂Cl₂/MeOH as eluent to afford 105 mg (80% yield) of a yellow/orangesolid. LC-MS: 364.2 [M+H], purity 99%.

Preparative Example 1900-K

The title compound was prepared according to the procedure outlined inPreparative Example 1800-K utilizing thiomethyl derivative (60 mg, 0.15mmol) from Preparative Example 1600-K to afford 21 mg (39% yield) of anoff-white solid. LC-MS: 364.1 [M+H], purity 90%.

Preparative Example 2000-K

The title compound was prepared according to the procedure outlined inPreparative Example 1800-K utilizing thiomethyl derivative (140 mg, 0.30mmol) from Preparative Example 1700-K to afford 30 mg (24% yield) ofyellow crystalline solid. LC-MS: 423.1 [M+H], purity 93%.

Preparative Example 2100-K

To a pressure tube charged with dichloride (5 g, 26.7 mmol) and a stirbar was added conc. NH₄OH (110 mL). The tube was sealed and heated to70° C. The mixture was stirred for 5 h, cooled to rt, and concentratedto dryness under reduced pressure. The resultant solid was suspended inH₂O (70 mL), filtered, and the solid washed with Et₂O (100 mL). Thecrude material was dried under reduced pressure to afford 4.2 g (93%yield) of a yellow solid that was used without purification. LC-MS:169.0 [M+H], purity 99%.

Preparative Example 2200-K

The title compound was prepared according to the procedure outlined inPreparative Example 2100-K except utilizing the 3-bromo derivative (2.0g, 7.5 mmol) to afford 1.7 g (92% yield) of a white solid. mp>215° C.;LC-MS: 249.0 [M+H], purity 99%.

Preparative Example 2300-K

To a solution of 7-amino adduct (4.2 g, 24.8 mmol) from PreparativeExample 2100-K in CH₂Cl₂ (50 mL) at rt was added Boc₂O (5.9 g, 27.3mmol) and DMAP (3.3 g, 27.3 mmol). The resulting solution was stirredfor 12 h at rt and was diluted with CH₂Cl₂ (50 mL) and sat. aq. NaHCO₃(25 mL). The layers were separated and the aqueous layer was extractedwith CH₂Cl₂ (2×30 mL). The combined organic layers were washed withbrine (1×30 mL), dried (Na₂SO₄), filtered and concentrated under reducedpressure. The crude product was purified by 40M Flash Elute using agradient (1 L of CH₂Cl₂ to 2.5 L of 1% MeOH (7M NH₃):CH₂Cl₂ to afford6.3 g (95% yield) of a white solid. LC-MS: 269.0 [M+H], purity 99%.

Preparative Example 2400-K

The title compound was prepared according to the procedure outlined inPreparative Example 2300-K except utilizing the 3-bromo derivative (2.0g, 8.1 mmol) from Preparative Example 2200-K to afford 2.5 g (89% yield)of a white solid; LC-MS: 349.1 [M+H], purity 95%.

Preparative Example 2500-K

To a solution of Boc derivative (0.10 g, 0.37 mmol) from PreparativeExample 2300-K in dioxane/DIPEA (3 ml/0.5 mL) at rt was addedbenzylamine (61 μL, 0.56 mmol) dropwise. The mixture was stirred atreflux for 12 h, cooled to rt, and concentrated under reduced pressure.The crude product was purified by preparative thin-layer chromatography(4×1000 μM plates) using a 30:1 mixture of CH₂Cl₂/MeOH as eluent toafford 65 mg (52% yield) of a yellow solid. LC-MS: 340.1 [M+H], purity99%.

Preparative Examples 2501-K-2525-K

Following the procedure set forth in Preparative Example 2500-K butsubstituting commercially available amines, the compounds in Column 3 ofTable 2500-K. TABLE 2500-K 1. Yield (%) Prep. Ex. Column 2 Column 3 2.LC-MS 2501-K

1. 12 2. 368.1 2502-K

1. 30 2. 346.1 2503-K

1. 69 2. 463.1 2504-K

1. 98 2. 464.1 2505-K

1. 46 2. 449.1 2506-K

1. 72 2. 412.1 2507-K

1. 94 2. 419.2 2508-K

1. 90 2. 499.1 2509-K

1. 47 2. 420.1 2510-K

1. 57 2. 427.1 2511-K

1. 85 2. 525.1 2512-K

1. 80 2. 525.1 2513-K

1. 53 2. 494.1 2514-K

1. 49 2. 434.1 2515-K

1. 95 2. 499.1 2516-K

1. 54 2. 513.1 2517-K

1. 84 2. 513.1 2618-K

1. 79 2. 499.1 2519-K

1. 78 2. 513.1 2520-K

1. 82 2. 513.1 2521-K

1. 92 2. 513.1 2522-K

1. 12 2. 485.3 2523-K

1. 28 2. 525.1 2524-K

1. 30 2. 525.1 2525-K

1. 89 2. 511.3

Preparative Example 2600-K

To a solution of Boc derivative (0.53 g, 1.27 mmol) from PreparativeExample 2507-K in MeOH (4 mL) at 0° C. was added KSCN (0.15 g, 1.52mmol) followed by Br₂ (75 μL, 1.52 mmol). The mixture was allowed towarm to rt, stir for 12 h, and was concentrated under reduced pressure.The crude residue was suspended in EtOAc (7 mL) and sat. aq. NaHCO₃ (2mL) and the layers were separated. The aqueous layer was extracted withEtOAc (2×7 mL) and the organic layers were combined. The organic layerwashed with brine (1×5 mL), dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The crude product was purified by columnchromatography using a 20:1 mixture of CH₂Cl₂/MeOH as eluent to afford0.37 g (65% yield) as a light yellow solid. LCMS: 476.3 [M+H} 99%purity.

Preparative Example 2700-K

To a solution of thiocyanate (100 mg, 0.21 mmol) from PreparativeExample 2600-K in THF (2 mL) at 0° C. was added Pd(PPh₃)₄ (24 mg, 0.021mmol) followed by dropwise addition of PhMgBr (1.0 M in THF, 1.26 mL).The mixture was stirred for 12 h at rt and was treated with sat. aqNH₄Cl (2 mL) and CH₂Cl₂ (5 mL). The layers were separated and theaqueous layer was extracted with CH₂Cl₂ (2×5 mL). The organic layerswere combined, washed with brine (1×3 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The crude product was purified bypreparative thin-layer chromatography (4×1000 μM plates) using a 3:1mixture of hexanes/EtOAc as eluent to afford 66 mg (60% yield) of ayellow semisolid. LC-MS: 527.1 [M+H], purity 99%.

Preparative Example 2800-K

To a solution of thiocyanate (100 mg, 0.21 mmol) from PreparativeExample 2600-K in MeOH (1.5 mL) at rt was added PPh₃ (55 mg, 0.21 mmol)in a single portion. The mixture was heated to reflux, stirred for 12 h,cooled and concentrated under reduced pressure. The crude product waspurified by preparative thin-layer chromatography (4×1000 μM plates)using a 3:1 mixture of hexanes/EtOAc as eluent to afford 66 mg (68%yield) of a white solid. LC-MS: 465.3 [M+H], purity 99%.

Preparative Example 2900-K

To a solution of thiocyanate (0.15 g, 0.32 mmol) from PreparativeExample 2600-K in EtOH (2.5 mL) at rt was added a 0.1 M soln. of KH₂PO₄(0.1 mL) followed by DTT (0.19 g, 1.26 mmol). The resulting mixture wasstirred for 12 h at rt and was concentrated under reduced pressure. Theresulting semisolid was dissolved in CH₂Cl₂ (5 mL) and washedsequentially with H₂O (3×2 mL) and brine (3×2 mL). The organic layer wasdried (Na₂SO₄), filtered, and concentrated under reduced pressure toafford 0.13 g (90% crude yield) of a light yellow semisolid. Thismaterial was taken on crude without purification.

Preparative Example 3000-K

To a solution of the crude sulfhydryl derivative (80 mg, 0.18 mmol) fromPreparative Example 2900-K in DMF (1.5 mL) at 0° C. was added K₂CO₃ (73mg, 0.53 mmol) followed by bromoethanol (37 μL, 0.53 mmol). Theresulting mixture was stirred for 72 h at rt where upon the mixture wasdiluted with EtOAc (5 mL) and water (2 mL). The layers were separatedand the organic layer washed with H₂O (3×2 mL) and brine (3×2 mL). Theorganic layer was dried (Na₂SO₄), filtered, and concentrated underreduced pressure to afford a yellow semisolid. The crude product waspurified by preparative thin-layer chromatography (4×1000 μM plates)using a 1:1 mixture of hexanes/EtOAc as eluent to afford 37 mg (41%yield) of a light brown semisolid. LC-MS: 495.1 [M+H], purity 99%.

Preparative Example 3100-K

The title compound was prepared according to the procedure outlined inPreparative Example 2300-K except utilizing the 3-nitro derivative (0.20g, 0.55 mmol) from Preparative Example 1800-K to afford 0.25 g (97%yield) of a yellow semisolid. LC-MS: 464.3 [M+H], purity 99%.

Preparative Example 3200-K

To a solution of 3-nitro adduct (70 mg, 0.15 mmol) from PreparativeExample 3100-K in MeOH (2 mL) at rt was added Pd/C (10%, 25 mg dry). Themixture was stirred under H₂ (1 atm) for 12 h whereupon the mixture wasfiltered thru a pad of Celite. The pad washed generously with MeOH (2×4mL) and the filtrate was concentrated under reduced pressure to afford64 mg (98% yield) of a pink solid. LC-MS: 434.1 [M+H], purity 90%.

Preparative Example 3300-K

To a solution of 3-amino adduct (60 mg, 0.14 mmol) from PreparativeExample 3200-K in CH₂Cl₂ (3 mL) at 0° C. was added Et₃N (29 μL, 0.21mmol) followed by AcCl (12 μL, 0.17 mmol). The resulting mixture wasstirred at rt for 12 h and was diluted with brine (3 mL) and CH₂Cl₂ (3mL). The layers were separated and the aqueous layer was extracted withCH₂Cl₂ (2×3 mL). The organic layers were combined, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The crude product waspurified by preparative thin-layer chromatography (2×1000 μM plates)using a 20:1 mixture of CH₂Cl₂/MeOH as eluent to afford 65 mg (68%yield) of a pink semisolid. LC-MS: 476.1 [M+H], purity 99%.

Preparative Example 3400-K

To a solution of 3-amino adduct (69 mg, 0.16 mmol) from PreparativeExample 3200-K in CH₂Cl₂ (1 mL)/AcOH (0.1 mL) at 0° C. was added2-thiophenecarboxaldehyde (18 μL, 0.19 mmol) followed by NaB(OAc)₃H (41mg, 0.19 mmol). The resulting mixture was stirred at rt for 12 h and wasdiluted with 1N NaOH (1 mL) and CH₂Cl₂ (3 mL). The layers were separatedand the aqueous layer was extracted with CH₂Cl₂ (2×3 mL). The organiclayers were combined, dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The crude product was purified by preparativethin-layer chromatography (2×1000 μM plates) using a 30:1 mixture ofCH₂Cl₂/MeOH as eluent to afford 97 mg (96% yield) of a brown/orange oil.LC-MS: 626.1 [M+H], purity 96%.

Preparative Example 3500-K

To a solution of 3-amino adduct (90 mg, 0.21 mmol) from PreparativeExample 3200-K in CH₂Cl₂ (1.5 mL) at 0° C. was added Et₃N (32 mL, 0.31mmol) followed by PhNCO (27 μL, 0.25 mmol). The resulting mixture wasstirred at rt for 12 h and was diluted with sat. aq. NaHCO₃ (2 mL) andCH₂Cl₂ (5 mL). The layers were separated and the aqueous layer wasextracted with CH₂Cl₂ (2×3 mL). The organic layers were combined, washedwith brine (1×3 mL), dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The crude product was purified by preparativethin-layer chromatography (2×1000 μM plates) using a 20:1 mixture ofCH₂Cl₂/MeOH as eluent to afford 110 mg (95% yield) of a white solid.LC-MS: 553.1 [M+H], purity 99%.

Preparative Example 3600-K

To a solution of 3-H adduct (0.15 g, 0.36 mmol) from Preparative Example2507-K in CH₃CN (2 mL) at 0° C. was added NCS (48 mg, 0.36 mmol) in asingle portion. The mixture was stirred for 3 h at 0° C. whereupon themixture was concentrated under reduced pressure. The crude product waspurified by preparative thin-layer chromatography (4×1000 μM plates)using a 2:1 mixture of hexanes/EtOAc as eluent to afford 0.16 g (98%yield) of a light yellow semisolid. LC-MS: 453.1 [M+H], purity 83%.

Preparative Example 3700-K

The title compound was prepared according to the procedure outlined inPreparative Example 3600-K utilizing the 3-H derivative (0.20 g, 0.55mmol) from Preparative Example 2507-K and NIS (0.13 g, 0.60 mmol) toafford 0.25 g (97% yield) of a yellow semisolid. LC-MS: 464.3 [M+H],purity 99%.

Example 100-K

TFA (0.3 mL) was added under N₂ to a stirred solution of the productfrom Preparative Example 700-K (18 mg, 0.04 mmol) in CH₂Cl₂ (1.5 mL).The mixture was stirred for 1 hr, the solvent was evaporated, and theresidue was mixed with solid Na₂CO₃ (100 mg) and 10:1 CH₂Cl₂/MeOH (2.0mL). The mixture was stirred under N₂ for 10 min, the solution waswithdrawn and loaded onto a silica gel preparative TLC plate, which wasthen developed with 10:1 CH₂Cl₂/7N NH₃ in MeOH. Pale yellow solid (5 mg,35%) was obtained. LC-MS: 380 [M+H]. Mp=106-109° C. SCH 773943

Examples 101-K-123-K

By essentially the same procedure set forth in Example 100-K onlysubstituting the compounds shown in Column 2 of Table 800-K, thecompounds shown in Column 3 of Table 800-K were prepared. TABLE 800-KEx. Column 2 Column 2 Data 101-K

LCMS: MH⁺ = 258 mp = 200- 202° C. 102-K

LCMS: MH⁺ = 300 mp = 104- 106° C. 103-K

LCMS: MH⁺ = 380 104-K

LCMS: MH⁺ = 300 mp = 191- 193° C. 105-K

106-K

mp = 157- 159° C. 107-K

LCMS: MH⁺ = 414 mp = 96-99° C. 108-K

LCMS: M2H⁺ = 394 109-K

LCMS: MH⁺ = 256 wax 110-K

LCMS: MH⁺ = 318 wax 111-K

LCMS: M⁺ = 379 mp = 247- 249° C. 112-K

LCMS: MH⁺ = 247 mp = 148- 150° C. 113-K

LCMS: MH⁺ = 327 mp = 114- 116° C. 114-K

LCMS: MH⁺ = 301 mp = 227- 229° C. 115-K

LCMS: MH⁺ = 379 mp = 156- 158° C. 118-K

LCMS: M⁺ = 376 mp = 95-98° C. 119-K

LCMS: M⁺ = 362 mp = 161- 163° C. 120-K

LCMS: M⁺ = 373 mp = 220- 222° C. 121-K

LCMS: M⁺ = 403 mp = 95-98° C. 122-K

get,0141 LCMS: M⁺ = 415 mp = 90-93° C. 123-K

LCMS: M⁺ = 332 mp = 200- 203° C. 124-K

125-K

126-K

Example 200-K

TFA (0.5 mL) was added under N₂ to a stirred solution of the productfrom Preparative Example 604-K (30 mg, 0.056 mmol) in CH₂Cl₂ (1.0 mL).The mixture was stirred for 4 hr, the solvent was evaporated, and theresidue was mixed with solid NaHCO₃ (200 mg) and 4:1 CH₂Cl₂/MeOH (5 mL).The mixture was stirred under N₂ for 30 min, additional CH₂Cl₂ (5 mL)was then added, the mixture was filtered through Celite, and the solventwas evaporated. Pale brown wax (31 mg) was obtained. LC-MS: 284 [M+2H].

Example 300-K

A mixture of the product from Example 112-K (70 mg, 0.29 mmol) andtert-butyl N-(2-oxoethyl)carbamate (45 mg, 0.29 mmol) in anhydrousCH₂Cl₂ (2 mL) was stirred under N₂ at 25° C. for 1 hr. Then NaBH(OAc)₃(106 mg, 0.50 mmol) was added, the mixture was stirred for 1 hr, andthen quenched with MeOH (2 mL). The solvents were evaporated and theresidue was purified by column chromatography on silica gel with 20:1CH₂Cl₂/7 N NH₃ in MeOH as eluent. White solid (84 mg, 76%) was obtained.LC-MS: 390 [M+H]. Mp=75-78° C.

Example 401-K-402-K

By essentially same procedure set forth in Example 300-K onlysubstituting the compounds shown in Column 2 of Table 900-K, thecompounds shown in Column of Table 900-K were prepared. TABLE 900-K Ex.Column 2 Column 3 Data 401-K

white solid LC-MS: 440 [M+]. 402-K

pale yellow wax. LC-MS: 443 [M + H].

Example 500-K

A solution of NBS (23 mg, 0.13 mmol) in anhydrous CH₃CN (1.0 mL) wasadded under N₂ to a stirred solution of the product from Example 300-K(50 mg, 0.13 mmol) in anhydrous CH₃CN (2.0 mL) and CH₂Cl₂ (1.0 mL). Themixture was stirred for 20 hr, the solvents were evaporated, and theresidue was purified by column chromatography on silica gel with 20:1CH₂Cl₂/MeOH as eluent. White solid (38 mg, 63%) was obtained. LC-MS: 468[M+]. Mp=150-152° C.

Example 500-K-502-K

By essentially same procedure set forth in Example 500-K, compoundsshown in Column 2 of Table 930-K were prepared. TABLE 930-K Ex. Column 2Data 501- K

colorless solid. LC-MS: 520 [M + H]. 502- K

pale yellow wax LC-MS: 523 [M + H]. SCH 785438

Example 701-K-702-K

By essentially same procedure set forth in Example 500-K onlysubstituting N-chlorosuccinimide, compounds shown in Column 2 of Table940-K were prepared. TABLE 940-K Ex. Column 2 Data 701-K

LCMS: M⁺ =mp = 702-K

white solid. LC-MS: 476 [M + H].

Example 800-K

TFA (0.4 mL) was added under N₂ to a stirred solution of the productfrom Example 500-K (30 mg, 0.064 mmol) in CH₂Cl₂ (2.0 mL). The mixturewas stirred for 1 hr, the solvent was evaporated, and the residue wasmixed with solid Na₂CO₃ (200 mg) and 10:1 CH₂Cl₂/MeOH (2.0 mL). Themixture was stirred under N₂ for 10 min, the solution was withdrawn andloaded onto a silica gel preparative TLC plate, which was then developedwith 10:1 CH₂Cl₂/7N NH₃ in MeOH. White solid (10 mg, 42%) was obtained.LC-MS: 368 [M+]. Mp=132-135° C.

Examples 801-K-803-K

By essentially same procedure set forth in Example 800-K, compoundsshown in Column 2 of Table 950-K were prepared: TABLE 950-K Ex. Column 2Data 801- K

pale yellow solid LC-MS: 421 [M + H]. Mp = 148- 150° C. 802- K

white solid LC- MS: 420 [M +H]. Mp =92-95° C. 803- K

pale yellow solid. LC-MS: 376 [M + H]. Mp = 138- 140° C.

Example 900-K

A solution of 37% HCHO (0.002 mL) in H₂O (0.02 mL) was added under N2 toa stirred solution of the product from Preparative Example 823-K (9 mg,0.027 mmol) in anhydrous THF (1 mL) an MeOH (0.3 mL) and then themixture was stirred under N₂ at 25° C. for 5 hr. Then NaBH(OAc)₃ (8 mg,0.038 mmol) was added and the mixture was stirred for 1 hr. The solventswere evaporated and the residue was purified by preparative TLC onsilica gel with 10:1 CH₂Cl₂/7 N NH₃ in MeOH as eluent. White solid 8 mg,85%) was obtained. LC-MS: 346 [M+]. Mp=92-95° C.

Preparative Example 3800-K

To a mixture of 7-amino adduct (65 mg, 0.19 mmol) from PreparativeExample 2500-K in CH₂Cl₂ (2 mL) at 0° C. was added TFA (1 mL) dropwise.The resulting mixture was stirred for 12 h at rt and was concentratedunder reduced pressure. The crude material was partitioned between EtOAc(5 mL) and sat. aq. Na₂CO₃ (2 mL) and the layers were separated. Theaqueous layer was extracted with EtOAc (2×5 mL) and the organic layerswere combined. The organic layer washed with brine (1×3 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The crudeproduct was purified by preparative thin-layer chromatography (4×1000 μMplates) using a 20:1 mixture of CH₂Cl₂/MeOH (7M NH₃) as eluent to afford41 mg (89% yield) as a brown solid. mp 111-113° C.; LC-MS: 240.0 [M+H],purity 98%.

Examples 1000-1025-K

By essentially the same procedure set forth in Preparative Example3800-K but utilizing the appropriate Boc derivatives, the compounds inColumn 2 of Table 1000-K were prepared. TABLE 1000-K 1. Yield (%) 2.LC-MS Ex. Column 2 3. mp 1000- K

1. 10 2. 297.1 3. 138-141 1001- K

1. 95 2. 320.1 3. 115-117 1002- K

1. 70 2. 327.1 3. 110-113 1003- K

1. 26 2. 325.1 3. 114-117 1004- K

1. 46 2. 325.1 3. 105-107 1005- K

1. 81 2. 394.1 3. 166-168 1006- K

1. 90 2. 334.1 3. 43-45 1007- K

1. 45 2. 299.1 3. 115-117 1008- K

1. 73 2. 313.1 3. 131-133 1009- K

1. 62 2. 313.1 3. 130-134 1010- K

1. 88 2. 299.1 3. 114-117 1011- K

1. 67 2. 313.1 3. 169-171 1012- K

1. 36 2. 313.1 3. 90-93 1013- K

1. 89 2. 313.1 3. 154-156 1014- K

1. 30 2. 285.3 1015- K

1. 83 2. 325.1 3. 115-117 1016- K

1. 80 2. 325.1 3. 105-107 1017- K

1. 64 2. 311.1 3. 98-102 1018- K

1. 79 2. 253.1 3. 188-190 1019- K

1. 20 2. 345.2 3. 127-129 1020- K

1. 70 2. 265.1 3. 120-122 1021- K

1. 87 2. 327.1 3. xxx-xxx 1022- K

1. 21 2. 295.1 3. xxx-xxx 1023- K

1. 17 2. 276.1 1024- K

1. 21 2. 295.1 3. xxx-xxx 1025- K

1. 20 2. 353.2 3. >200

Example 1100-K

To a solution of 7-amino adduct (20 mg, 0.067 mmol) from Example 1010-Kin CH₃CN at 0° C. was added NBS (12 mg, 0.067 mmol) in a single portion.The mixture was stirred for 2 hours at rt and was concentrated underreduced pressure. The crude product was purified by preparativethin-layer chromatography (2×1000 μM plates) using a 10:1 mixture ofCH₂Cl₂/MeOH(7M NH₃) as eluent to afford 20 mg (79% yield) as a lightorange solid. mp 159-161° C. LC-MS: 377.1 [M+H], purity 99%.

Examples 1101-K-1112-K

Following the procedure set forth in Example 1100-K and utilizing eitherNBS, NCS, or NIS the compounds in Column 3 of Table 1100-K wereprepared. TABLE 1100-K 1. Yield (%) Prep. 2. LC-MS Ex. Column 2 Column 33. mp (° C.) 1101-K NCS

1. 41 2. 333.2 3. 123-125 1102-K NCS

1. 64 2. 333.2 3. 122-125 1103-K NBS

1. 66 2. 377.2 3. 159-161 1104-K NBS

1. 38 2. 344.1 3. xxx-xxx 1105-K NBS

1. 89 2. 403.1 3. 66-68 1106-K NBS

1. 90 2. 403.1 3. 170-172 1107-K NBS

1. 53 2. 389.1 3. xxx-xxx 1108-K NBS

1. 48 2. 391.1 3. 142-144 1109-K NBS

1. 59 2. 407.2 3. 156-158 1110-K NBS

1. 75 2. 375.1 3. 134-136 1111-K NBS

1. 63 2. 333.1 3. 153-155 1112-K NCS

1. 15 2. 287.1 3. >200

Preparative Example 3900-K

To a solution of 7-methoxy adduct (0.10 g, 0.30 mmol) from PreparativeExample 402-K in AcOH at rt was added morpholine (29 μL, 0.33 mmol)followed by 40% formaldehyde in H₂O (1 mL). The resulting mixture wasstirred at rt for 12 h whereupon the mixture was concentrated underreduced pressure. The crude semisolid was partitioned between CH₂Cl₂ (5mL) and sat. aq. NaHCO₃ (3 mL) and the layers were separated. Theaqueous layer was extracted with CH₂Cl₂ (2×5 mL) and the organic layerswere combined. The organic layer was washed with brine (1×3 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure to afford0.11 g (84% crude yield) of a light yellow semisolid. LC-MS: 432.1[M+H], purity 94%.

Preparative Example 4000-K

To a pressure tube charged with a stir bar was added 7-methoxy (96 mg,0.22 mmol) from Preparative Example 3900-K followed by 2M NH₃ in IPA (2mL) and conc. NH₄OH (2 mL). The tube was capped and was heated to 85° C.and stirred for 14 h. The mixture was cooled to rt, concentrated underreduced pressure, and placed under high vacuum to remove tracevolatiles. The crude product was purified by preparative thin-layerchromatography (4×1000 μM) plates using a 10:1 mixture of CH₂Cl₂/MeOH aseluent to afford 40 mg (43% yield) of a yellow semisolid. LC-MS: 417.1[M+H], purity 89%.

Example 1200-K

To a mixture of 7-amino adduct (40 mg, 0.096 mmol) from PreparativeExample 4000-K was added 4N HCl/dioxane (3 mL) dropwise. The resultingmixture was stirred for 12 h at rt and was concentrated under reducedpressure. The crude material was taken up in CH₂Cl₂ (5 mL) and wasconcentrated under reduced pressure and this procedure was repeated 3×.The resulting solid was triturated with Et₂O (3×3 m) and wasconcentrated under reduced pressure to afford 26 mg (75% yield) of alight yellow solid. mp 190-193° C.; LC-MS: 317.1 [M+H], purity >90%.

Preparative Example 4100-K

The title compound was prepared from 7-chloro adduct (2.6 g, 7.7 mmol)from Preparative Example 200-K and NaSMe (0.65 g, 9.3 mmol) according tothe procedure outlined in Preparative Example 1 to afford 2.6 g (98%yield) of a pale white solid. LC-MS: 349.1 [M+H], purity 98%.

Preparative Example 4200-K

The above compound was prepared from 7-thiomethyl adduct (1.1 g, 3.1mmol) from Preparative Example 4100-K according to the procedureoutlined in Example 1 to afford 0.70 g (90% yield) of a yellowsemisolid. LC-MS: 249.1 [M+H], purity 98%.

Preparative Example 4300-K

To a solution of thiomethyl adduct (1.3 g, 3.13 mmol) from PreparativeExample 4200-K in CH₂Cl₂ (20 mL) at 0° C. was added Et₃N (0.65 mL, 4.7mmol) followed by CbzCl (0.48 mL, 3.4 mmol). The resulting mixture wasstirred for 12 h at rt and the mixture was diluted CH₂Cl₂ (15 mL) andsat. aq. NaHCO₃ (5 mL) and the layers were separated. The aqueous layerwas extracted with CH₂Cl₂ (2×10 mL) and the organic layers werecombined. The organic layer washed with brine (1×5 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The crude product waspurified by flash chromatography using CH₂Cl₂ as eluent to afford 0.96 g(80% yield) of a yellow oil. LC-MS: 383.1 [M+H], purity 91%.

Preparative Example 4400-K

To a solution of 7-thiomethyl adduct (0.29 g, 0.75 mmol) fromPreparative Example 4300-K in DMF (3 ml) at 0° C. was added POCl₃ (0.10mL, 1.1 mmol). The resulting mixture was allowed to warm to rt and stirfor 12 h. The mixture was cooled to 0° C. and was treated with ice water(2 ml) and CH₂Cl₂ (5 mL). The layers were separated and the aqueouslayer was extracted with CH₂Cl₂ (2×5 mL). The organic layers werecombined, washed with brine (1×5 mL). The organic layer was dried(Na₂SO₄), filtered, and concentrated under reduced pressure to afford0.28 g (91% yield) of a yellow solid. LC-MS: 433.2 [M+H], purity 84%.

Preparative Example 4500-K

To a mixture of benzyltriphenylphosphonium bromide (0.64 g, 1.48 mmol)and NaH (59 mg, 1.48 mmol) in dry THF (3 mL) at rt was added thiomethyladduct (0.21 g, 0.50 mmol) from Preparative Example 4400-K. The mixturewas heated at reflux for 12 h, cooled to rt, and diluted with CH₂Cl₂ (5mL) and brine (2 mL). The layers were separated and the aqueous layerwas extracted with CH₂Cl₂ (2×5 mL). The organic layers were combined,washed with brine (1×5 mL). The organic layer was dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The crude product waspurified by preparative thin-layer chromatography (2×1000 μM plates)using a 1:1 mixture of hexanes/EtOAc as eluent to afford 100 mg (42%yield) as a light orange solid.

Preparative Example 4600-K

The title compound was prepared from 7-thiomethyl adduct (0.10 g, 0.21mmol) from Preparative Example 4500-K according to the procedureoutlined in Preparative Example 1500-K to afford 0.11 g (quantitativeyield) of a yellow solid. LC-MS: 501.3 [M+H], purity 63%.

Preparative Example 4700-K

The title compound was prepared from 7-sulfoxide adduct (0.11 g, 0.21mmol) from Preparative Example 4600-K according to the procedureoutlined in Preparative Example 1800-K to afford 83 mg (40% yield) of ayellow solid. LC-MS: 454.1 [M+H], purity 90%.

Example 1300-K

To a solution of 7-amino adduct (38 mg, 0.083 mmol) from PreparativeExample 4700-K in CH₃CN (3 mL) at 0° C. was added TMSI (0.12 mL, 0.83mmol) dropwise. The mixture was stirred for 12 h at rt whereupon 1N NaOH(2 mL) was added. The mixture was extracted with EtOAc (5×5 mL) and theorganic layers were combined. The organic layer washed with brine (1×3mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure.The crude product was purified by preparative thin-layer chromatography(2×1000 μM plates) using a 10:1 mixture of CH₂Cl₂/MeOH(7M NH₃) as eluentto afford 15 mg (56% yield) as a light yellow solid. mp 144-146° C.LCMS: 319.4 [M+H} 90% purity.

Example 1400-K-1500-K

The compound prepared in Example 118-K was separated into individualenantiomers by semi-preparative HPLC using a ChiralPak OD column (flowrate=9 mL/min) and a gradient of 85:15 hexanes:isopropanol with 0.2%diethylamine to 75:25 hexanes:isopropanol solution with 0.2%diethylamine as eluent.

Example 1400-K

(first eluting isomer, (R)): LCMS: M⁺=376.

Example 1500-K

(second eluting isomer, (S)): M⁺=LCMS: 376:

Example 1600K-, Example 1700-K, Example 1800-K and Example 1900-K

By a similar procedure, the following compounds can also be prepared:

Assay:BACULOVIRUS CONSTRUCTIONS: Cyclins A and E were cloned into pFASTBAC(Invitrogen) by PCR, with the addition of a GluTAG sequence (EYMPME) atthe amino-terminal end to allow purification on anti-GluTAG affinitycolumns. The expressed proteins were approximately 46 kDa (cyclin E) and50 kDa (cyclin A) in size. CDK2 was also cloned into pFASTBAC by PCR,with the addition of a haemaglutinin epitope tag at the carboxy-terminalend (YDVPDYAS). The expressed protein was approximately 34 kDa in size.ENZYME PRODUCTION: Recombinant baculoviruses expressing cyclins A, E andCDK2 were infected into SF9 cells at a multiplicity of infection (MOI)of 5, for 48 hrs. Cells were harvested by centrifugation at 1000 RPM for10 minutes. Cyclin-containing (E or A) pellets were combined with CDK2containing cell pellets and lysed on ice for 30 minutes in five timesthe pellet volume of lysis buffer containing 50 mM Tris pH 8.0, 0.5%NP40, 1 mM DTT and protease/phosphatase inhibitors (Roche DiagnosticsGmbH, Mannheim, Germany). Mixtures were stirred for 30-60 minutes topromote cyclin-CDK2 complex formation. Mixed lysates were then spun downat 15000 RPM for 10 minutes and the supernatant retained. 5 ml ofanti-GluTAG beads (for one liter of SF9 cells) were then used to capturecyclin-CDK2 complexes. Bound beads were washed three times in lysisbuffer. Proteins were competitively eluted with lysis buffer containing100-200 ug/mL of the GluTAG peptide. Eluate was dialyzed overnight in 2liters of kinase buffer containing 50 mM Tris pH 8.0, 1 mM DTT, 10 mMMgCl2, 100 uM sodium orthovanadate and 20% glycerol. Enzyme was storedin aliquots at −70° C.IN VITRO KINASE ASSAY: CDK2 kinase assays (either cyclin A orE-dependent) were performed in low protein binding 96-well plates(Corning Inc, Corning, N.Y.). Enzyme was diluted to a finalconcentration of 50 μg/ml in kinase buffer containing 50 mM Tris pH 8.0,10 mM MgCl₂, 1 mM DTT, and 0.1 mM sodium orthovanadate. The substrateused in these reactions was a biotinylated peptide derived from HistoneH1 (from Amersham, UK). The substrate was thawed on ice and diluted to 2μM in kinase buffer. Compounds were diluted in 10% DMSO to desirableconcentrations. For each kinase reaction, 20 μl of the 50 μg/ml enzymesolution (1 μg of enzyme) and 20 μl of the 1 μM substrate solution weremixed, then combined with 10 μl of diluted compound in each well fortesting. The kinase reaction was started by addition of 50 μl of 4 μMATP and 1 μCi of 33P-ATP (from Amersham, UK). The reaction was allowedto run for 1 hour at room temperature. The reaction was stopped byadding 200 μl of stop buffer containing 0.1% Triton X-100, 1 mM ATP, 5mM EDTA, and 5 mg/ml streptavidine coated SPA beads (from Amersham, UK)for 15 minutes. The SPA beads were then captured onto a 96-well GF/Bfilter plate (Packard/Perkin Elmer Life Sciences) using a Filtermateuniversal harvester (Packard/Perkin Elmer Life Sciences.). Non-specificsignals were eliminated by washing the beads twice with 2M NaCl thentwice with 2 M NaCl with 1% phosphoric acid. The radioactive signal wasthen measured using a TopCount 96 well liquid scintillation counter(from Packard/Perkin Elmer Life Sciences).

IC₅₀ DETERMINATION: Dose-response curves were plotted from inhibitiondata generated, each in duplicate, from 8 point serial dilutions ofinhibitory compounds. Concentration of compound was plotted against %kinase activity, calculated by CPM of treated samples divided by CPM ofuntreated samples. To generate IC₅₀ values, the dose-response curveswere then fitted to a standard sigmoidal curve and IC₅₀ values werederived by nonlinear regression analysis. The thus-obtained IC₅₀ valuesfor the compounds of the invention are shown in Table 87. These kinaseactivities were generated by using cyclin A or cyclin E using theabove-described assay. TABLE 87 CMPD Example IC₅₀ (μM)

1 0.020 0.029

3 0.032 0.024

4 0.011

5 0.021

8 0.003

6 0.064 0.029

7 0.01 0.006

10 0.042

12 0.17

16 0.62

1 5.6

3 0.14

As demonstrated above by the assay values, the compounds of the presentinvention exhibit excellent CDK inhibitory properties.

While the present invention has been described with in conjunction withthe specific embodiments set forth above, many alternatives,modifications and other variations thereof will be apparent to those ofordinary skill in the art. All such alternatives, modifications andvariations are intended to fall within the spirit and scope of thepresent invention. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00001 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00002 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00003 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00004 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00005 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00006 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00007 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00008 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00009 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00010 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00011 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00012 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00013 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00014 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00015 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00016 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00017 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00018 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00019 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00020 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00021 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00022 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00023 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00024 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00025 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00026 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00027 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00028 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00029 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00030 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00031 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00032 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00033 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00034 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00035 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00036 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00037 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00038 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00039 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00040 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00041 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00042 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070281951A1-20071206-T00043 Please refer to the end of thespecification for access instructions. LENGTHY TABLE The patentapplication contains a lengthy table section. A copy of the table isavailable in electronic form from the USPTO web site(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20070281951A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A method of inhibiting tumor growth in a patient comprisingadministering a therapeutically effective amount of at least onecompound, or a pharmaceutically acceptable salt, solvate, ester orprodrug thereof, to said patient, wherein said compound is selected fromthe group consisting of the compounds of the formulas:


2. The method of claim 1, wherein said tumor is selected from the groupconsisting of: tumor of the bladder, breast (including BRCA-mutatedbreast cancer, colorectal, colon, kidney, liver, lung, small cell lungcancer, non-small cell lung cancer, head and neck, esophagus, bladder,gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, andskin, including squamous cell carcinoma; leukemia, acute lymphocyticleukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-celllymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma,mantle cell lymphoma, myeloma and Burkett's lymphoma; chroniclymphocytic leukemia (“CLL”), acute and chronic myelogenous leukemia,myelodysplastic syndrome and promyelocytic leukemia; fibrosarcoma,rhabdomyosarcoma; head and neck, mantle cell lymphoma, myeloma;astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glialtumors, astrocytoma, hepatocellular carcinoma, gastrointestinal stromaltumors (“GIST”) and schwannomas; melanoma, multiple myeloma, seminoma,teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma,thyroid follicular cancer and Kaposi's sarcoma.
 3. A method ofinhibiting tumor growth in a mammal, comprising administering to saidmammal an amount of a first compound, or a pharmaceutically acceptablesalt, ester or prodrug thereof; and an amount of at least one secondcompound, said second compound being an anti-cancer agent; wherein theamounts of the first compound and said second compound result in atherapeutic effect, wherein said first compound is selected from thegroup consisting of the compounds of the formulas:


4. The method of claim 3, further comprising radiation therapy.
 5. Themethod of claim 3, wherein said anti-cancer agent is selected from thegroup consisting of a cytostatic agent, cisplatin, doxorubicin, Caelyx®,Myocet®, Doxil®, taxotere, taxol, etoposide, irinotecan, camptostar,topotecan, paclitaxel, docetaxel, epothilones, tamoxifen,5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH66336, R115777®, L778,123®, BMS 214662®, Iressa®, Tarceva®, antibodiesto EGFR, antibodies to IGFR, Gleevec®, intron, ara-C, adriamycin,cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, ispinesib,SB-743921, GSK-923295, Triethylenethiophosphoramine, Busulfan,Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine,Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate,oxaliplatin, leucovirin, ELOXATIN™, Pentostatine, Vinblastine,Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin,Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C,L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol,Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate,Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone,Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea,Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, bortezomib (“Velcade”),Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal,Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant,Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225®, satriplatin,Mylotarg® (Gemtuzumab ozogamicin), Avastin® (bevacizumab), Alimta®(pemetrexed), panitubimab, Sutent® (sunitinib), sorafenib, Sprycel®(dastinib), nilotinib, Tykerb® (lapatinib) and Campath.
 6. A method ofinhibiting tumor growth in a mammal, comprising administering to saidmammal an amount of a first compound, or a pharmaceutically acceptablesalt, solvate, ester or prodrug thereof; and an amount of temozolomide;wherein the amounts of the first compound and said temozolomide resultin a therapeutic effect, wherein said first compound is selected fromthe group consisting of the compounds of the formulas:


7. The method of claim 6, further comprising radiation therapy.
 8. Amethod inhibiting tumor growth in a mammal, comprising administering tosaid mammal a composition comprising a therapeutically effective amountof a compound, or a pharmaceutically acceptable salt, solvate, ester orprodrug thereof, wherein said compound is selected from the groupconsisting of the compounds of the formulas:


9. The method of claim 8, further comprising administering radiationtherapy.
 10. The method of claim 8, wherein said tumor is selected fromthe group consisting of: tumor of the bladder, breast (includingBRCA-mutated breast cancer, colorectal, colon, kidney, liver, lung,small cell lung cancer, non-small cell lung cancer, head and neck,esophagus, bladder, gall bladder, ovary, pancreas, stomach, cervix,thyroid, prostate, and skin, including squamous cell carcinoma;leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia,B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkinslymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma andBurkett's lymphoma; chronic lymphocytic leukemia (“CLL”), acute andchronic myelogenous leukemia, myelodysplastic syndrome and promyelocyticleukemia; fibrosarcoma, rhabdomyosarcoma; head and neck, mantle celllymphoma, myeloma; astrocytoma, neuroblastoma, glioma, glioblastoma,malignant glial tumors, astrocytoma, hepatocellular carcinoma,gastrointestinal stromal tumors (“GIST”) and schwannomas; melanoma,multiple myeloma, seminoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi'ssarcoma.
 11. A method inhibiting tumor growth in a mammal, comprisingadministering to said mammal a composition comprising (i) atherapeutically effective amount of a first compound, or apharmaceutically acceptable salt, solvate, ester or prodrug thereof, and(ii) an anti-cancer agent, wherein the amounts of said first compoundand anti-cancer agent result in therapeutic effect, further wherein saidfirst compound is selected from the group consisting of the compounds ofthe formulas:


12. The method of claim 11, wherein said anti-cancer agent is selectedfrom the group consisting of a cytostatic agent, cisplatin, doxorubicin,Caelyx®, Myocet®, Doxil®, taxotere, taxol, etoposide, irinotecan,camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen,5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH66336, R115777®, L778,123®, BMS 214662®, Iressa®, Tarceva®, antibodiesto EGFR, antibodies to IGFR, Gleevec®, intron, ara-C, adriamycin,cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, ispinesib,SB-743921, GSK-923295, Triethylenethiophosphoramine, Busulfan,Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine,Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate,oxaliplatin, leucovirin, ELOXATIN™, Pentostatine, Vinblastine,Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin,Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C,L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol,Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate,Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone,Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea,Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, bortezomib (“Velcade”),Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal,Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant,Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225®, satriplatin,Mylotarg® (Gemtuzumab ozogamicin), Avastin® (bevacizumab), Alimta®(pemetrexed), panitubimab, Sutent® (sunitinib), sorafenib, Sprycel®(dastinib), nilotinib, Tykerb® (lapatinib) and Campath.
 13. A method oftreating a cancer in a patient, comprising administering to said patienta therapeutically effective amount of at least one compound, or apharmaceutically acceptable salt, solvate, ester or prodrug thereof, tosaid patient, wherein said compound is selected from the groupconsisting of the compounds of the formulas:


14. A method of treating a cancer in a patient, comprising administeringto said patient a composition comprising a therapeutically effectiveamount of at least one compound, or a pharmaceutically acceptable salt,solvate, ester or prodrug thereof, to said patient, wherein saidcompound is selected from the group consisting of the compounds of theformulas:


15. The method of claim 14, wherein said composition further comprisesan anti-cancer agent.
 16. The method of claim 14, further comprisingadministration of radiation therapy.
 17. The method of claim 15, whereinsaid anti-cancer agent is selected from the group consisting of acytostatic agent, cisplatin, doxorubicin, Caelyx®, Myocet®, Doxil®,taxotere, taxol, etoposide, irinotecan, camptostar, topotecan,paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil,methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777®,L778,123®, BMS 214662®, Iressa®, Tarceva®, antibodies to EGFR,antibodies to IGFR, Gleevec®, intron, ara-C, adriamycin, cytoxan,gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan,Chlorambucil, Pipobroman, Triethylenemelamine, ispinesib, SB-743921,GSK-923295, Triethylenethiophosphoramine, Busulfan, Carmustine,Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine,6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin,leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine,Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Epirubicin,Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase,Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, bortezomib (“Velcade”),Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal,Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant,Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225®, satriplatin,Mylotarg® (Gemtuzumab ozogamicin), Avastin® (bevacizumab), Alimta®(pemetrexed), panitubimab, Sutent® (sunitinib), sorafenib, Sprycel®(dastinib), nilotinib, Tykerb® (lapatinib) and Campath.
 18. Acomposition comprising (i) at least one compound selected from the groupconsisting of satriplatin, Mylotarg® (Gemtuzumab ozogamicin), Avastin®(bevacizumab), panitubimab, Sutent® (sunitinib), sorafenib, Sprycel®(dastinib), nilotinib, Tykerb® (lapatinib) and (ii) at least onecompound, or a pharmaceutically acceptable salt, solvate, ester orprodrug thereof, wherein said at least one compound in (ii) is selectedfrom the group consisting of the compounds of the formulas:


19. A method of inhibiting cyclin dependent kinase in a patient,comprising administering the composition of claim 18 to said patient.20. A method of treating a disease with said composition of claim 18,wherein said disease is selected from the group consisting of: tumor ofthe bladder, breast (including BRCA-mutated breast cancer, colorectal,colon, kidney, liver, lung, small cell lung cancer, non-small cell lungcancer, head and neck, esophagus, bladder, gall bladder, ovary,pancreas, stomach, cervix, thyroid, prostate, and skin, includingsquamous cell carcinoma; leukemia, acute lymphocytic leukemia, acutelymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkinslymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle celllymphoma, myeloma and Burkett's lymphoma; chronic lymphocytic leukemia(“CLL”), acute and chronic myelogenous leukemia, myelodysplasticsyndrome and promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma;head and neck, mantle cell lymphoma, myeloma; astrocytoma,neuroblastoma, glioma, glioblastoma, malignant glial tumors,astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumors(“GIST”) and schwannomas; melanoma, multiple myeloma, seminoma,teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma,thyroid follicular cancer and Kaposi's sarcoma.
 21. A method of treatinga disease with a composition, wherein said disease is selected from thegroup consisting of: BRCA-mutated breast cancer, colorectal cancer,bladder cancer, chronic lymphocytic leukemia (“CLL”), glioblastoma,malignant glial tumors, astrocytoma, hepatocellular carcinoma,gastrointestinal stromal tumors (“GIST”) and multiple myeloma, andfurther wherein said composition comprises a pharmaceutically acceptablecarrier and at least one compound, or a pharmaceutically acceptablesalt, solvate, ester or prodrug thereof, wherein said at least onecompound is selected from the group consisting of the compounds of theformulas: